If the tumor can be removed surgically, patients may receive adjuvant chemotherapy or radiation therapy after the operation to improve the chances of cure. If the tissue margins are negative (i.e. the tumor has been totally ), adjuvant therapy is of uncertain benefit. Both positive and negative results have been reported with adjuvant radiation therapy in this setting, and no prospective randomized controlled trials have been conducted as of March 2007. Adjuvant chemotherapy appears to be ineffective in patients with completely resected tumors. The role of combined chemoradiotherapy in this setting is unclear. However, if the tumor tissue margins are positive, indicating that the tumor was not completely removed via surgery, then adjuvant therapy with radiation and possibly chemotherapy is generally recommended based on the available data.

The majority of cases of cholangiocarcinoma present as inoperable (unresectable) disease in which case patients are generally treated with palliative chemotherapy, with or without radiotherapy. Chemotherapy has been shown in a randomized controlled trial to improve quality of life and extend survival in patients with inoperable cholangiocarcinoma. There is no single chemotherapy regimen which is universally used, and enrollment in clinical trials is often recommended when possible. Chemotherapy agents used to treat cholangiocarcinoma include 5-fluorouracil with leucovorin, gemcitabine as a single agent, or gemcitabine plus cisplatin, irinotecan, or capecitabine. A small pilot study suggested possible benefit from the tyrosine kinase inhibitor erlotinib in patients with advanced cholangiocarcinoma.

These lesions rarely require surgery unless they are symptomatic or the diagnosis is in question. Since these lesions do not have malignant potential, long-term observation is unnecessary. Surgery can include the removal of the head of the pancreas (a pancreaticoduodenectomy), removal of the body and tail of the pancreas (a distal pancreatectomy), or rarely removal of the entire pancreas (a total pancreatectomy). In selected cases the surgery can be performed using minimally invasive techniques such as laparoscopy.

Treatment is variable, both due to its rarity and to its frequently slow-growing nature. Treatment ranges from watchful waiting to debulking and hyperthermic intraperitoneal chemotherapy (HIPEC, also called intraperitoneal hyperthermic chemotherapy, IPHC) with cytoreductive surgery.

The treatment of choice for main-duct IPMNs is resection due to approximately 50% chance of malignancy. Side-branch IPMNs are occasionally monitored with regular CT or MRIs, but most are eventually resected, with a 30% rate of malignancy in these resected tumors. Survival 5 years after resection of an IPMN without malignancy is approximately 80%, 85% with malignancy but no lymph node spread and 0% with malignancy spreading to lymph nodes. Surgery can include the removal of the head of the pancreas (a pancreaticoduodenectomy), removal of the body and tail of the pancreas (a distal pancreatectomy), or rarely removal of the entire pancreas (a total pancreatectomy). In selected cases the surgery can be performed using minimally invasive techniques such as laparoscopy or robotic surgery. A study using Surveillance, Epidemiology, and End Result Registry (SEER) data suggested that increased lymph node counts harvested during the surgery were associated with better survival in invasive IPMN patients.

The standard of care for mucinous adenocarcinoma with clinical condition PMP involves cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC), by surgical oncologists who specialize in treating PMP. Some surgeons also apply early post-operative intraperitonial chemotherapy (EPIC), adjunct to surgical cytoreduction and HIPEC. In situations where surgery is not required immediately, patients can be monitored via CT scans, tumor marker laboratory tests, and physical symptoms, to determine when, and if, surgery is warranted. Although some surgical procedures may be rather extensive, patients can and do recover from surgery, and the majority of these patients can and do live productive lives.

In debulking, the surgeon attempts to remove as much tumor as possible. CRS or cytoreductive surgery involves surgical removal of the peritoneum and any adjacent organs which appear to have tumor seeding. Since the mucus tends to pool at the bottom of the abdominal cavity, it is common to remove the ovaries, fallopian tubes, uterus, and parts of the large intestine. Depending upon the spread of the tumor, other organs might be removed, including but not limited to the gallbladder, spleen, and portions of the small intestine and/or stomach. For organs that cannot be removed safely (like the liver), the surgeon strips off the tumor from the surface.

Partial surgical resection is the optimal treatment for hepatocellular carcinoma (HCC) when patients have sufficient hepatic function reserve. Increased risk of complications such as liver failure can occur with resection of cirrhotic (i.e. less-than-optimally functional) livers. 5-year survival rates after resection have massively improved over the last few decades and can now exceed 50%. However, recurrence rates after resection can exceed 70%, whether due to spread of the initial tumor or formation of new tumors . Liver transplantation can also be considered in cases of HCC where this form of treatment can be tolerated and the tumor fits specific criteria (such as the Milan criteria). In general, patients who are being considered for liver transplantation have multiple hepatic lesions, severe underlying liver dysfunction, or both. Less than 30-40% of individuals with HCC are eligible for surgery and transplant because the cancer is often detected at a late stage. Also, HCC can progress during the waiting time for liver transplants, which can prevent transplant due to the strict criteria.

Percutaneous ablation is the only non-surgical treatment that can offer cure. There are many forms of percutaneous ablation, which consist of either injecting chemicals into the liver (ethanol or acetic acid) or producing extremes of temperature using radio frequency ablation, microwaves, lasers or cryotherapy. Of these, radio frequency ablation has one of the best reputations in HCC, but the limitations include inability to treat tumors close to other organs and blood vessels due to heat generation and the heat sink effect, respectively. In addition, long-term of outcomes of percutaneous ablation procedures for HCC have not been well studied. In general, surgery is the preferred treatment modality when possible.

Systemic chemotherapeutics are not routinely used in HCC, although local chemotherapy may be used in a procedure known as transarterial chemoembolization. In this procedure, cytotoxic drugs such as doxorubicin or cisplatin with lipiodol are administered and the arteries supplying the liver are blocked by gelatin sponge or other particles. Because most systemic drugs have no efficacy in the treatment of HCC, research into the molecular pathways involved in the production of liver cancer produced sorafenib, a targeted therapy drug that prevents cell proliferation and blood cell growth. Sorafenib obtained FDA approval for the treatment of advanced hepatocellular carcinoma in November 2007. This drug provides a survival benefit for advanced HCC.

Radiotherapy is not often used in HCC because the liver is not tolerant to radiation. Although with modern technology it is possible to provide well-targeted radiation to the tumor, minimizing the dose to the rest of the liver. Dual treatments of radiotherapy plus chemoembolization, local chemotherapy, systemic chemotherapy or targeted therapy drugs may show benefit over radiotherapy alone.

Resection is an option in cholangiocarcinoma, but less than 30% of cases of cholangiocarcinoma are resectable at diagnosis. After surgery, recurrence rates are up to 60%. Liver transplant may be used where partial resection is not an option, and adjuvant chemoradiation may benefit some cases.

60% of cholangiocarcinomas form in the perihilar region and photodynamic therapy can be used to improve quality of life and survival time in these unresectable cases. Photodynamic therapy is a novel treatment that utilitizes light activated molecules to treat the tumor. The compounds are activated in the tumor region by laser light, which causes the release of toxic reactive oxygen species, killing tumor cells.

Systemic chemotherapies such as gemcitabine and cisplatin are sometimes used in inoperable cases of cholangiocarcinoma.

Radio frequency ablation, transarterial chemoembolization and internal radiotherapy (brachytherapy) all show promise in the treatment of cholangiocarcinoma.

Radiotherapy may be used in the adjuvant setting or for palliative treatment of cholangiocarcinoma.

Surgical removal of the tumor, adjuvant chemotherapy prior to tumor removal, and liver transplantation have been used to treat these cancers. Primary liver transplantation provides high, long term, disease-free survival rate in the range of 80%, in cases of complete tumor removal and adjuvant chemotherapy survival rates approach 100%. The presence of metastases is the strongest predictor of a poor prognosis.

The most common and most effective treatment is surgical removal of the gallbladder (cholecystectomy) with part of liver and lymph node dissection. However, with gallbladder cancer's extremely poor prognosis, most patients will die within a year of surgery. If surgery is not possible, endoscopic stenting of the biliary tree can reduce jaundice and a stent in stomach may relieve vomiting. Chemotherapy and radiation may also be used with surgery. If gall bladder cancer is diagnosed after cholecystectomy for stone disease (incidental cancer), reoperation to remove part of liver and lymph nodes is required in most cases. When it is done as early as possible, patients have the best chance of long-term survival and even cure.

No pharmacologic treatment has been approved by the U.S. Food and Drug Administration for PSC. Some experts recommend a trial of ursodeoxycholic acid (UDCA), a bile acid occurring naturally in small quantities in humans, as it has been shown to lower elevated liver enzyme numbers in patients with PSC and has proven effective in other cholestatic liver diseases. However, UDCA has yet to be shown to clearly lead to improved liver histology and survival. Guidelines from the American Association for the Study of Liver Diseases and the American College of Gastroenterology do not support the use of UDCA but guidelines from the European Association for the Study of the Liver do endorse the use of moderate doses (13-15 milligrams per kilogram) of UDCA for PSC.

Supportive treatment for PSC symptoms is the cornerstone of management. These therapies are aimed at relieving symptoms such as itching with antipruritics (e.g. bile acid sequestrants such as (cholestyramine)); antibiotics to treat episodes of acute cholangitis; and vitamin supplements, as people with PSC are often deficient in fat-soluble vitamins (vitamin A, vitamin D, vitamin E, and vitamin K).

ERCP and specialized techniques may also be needed to help distinguish between a benign PSC stricture and a bile duct cancer (cholangiocarcinoma).

Liver transplantation is the only proven long-term treatment of PSC, although only a fraction of individuals with PSC will need it. Indications for transplantation include recurrent bacterial cholangitis, decompensated cirrhosis, hepatocellular carcinoma, hilar cholangiocarcinoma, and complications of portal hypertension. Not all patients are candidates for liver transplantation, and some will experience disease recurrence afterward.

The treatment depends on clinical features and the location of the biliary abnormality. When the disease is localized to one hepatic lobe, hepatectomy relieves symptoms and appears to remove the risk of malignancy. Good evidence suggests that malignancy complicates Caroli disease in roughly 7% of cases.

Antibiotics are used to treat the inflammation of the bile duct, and ursodeoxycholic acid is used for hepatolithiasis. Ursodiol is given to treat cholelithiasis. In diffuse cases of Caroli disease, treatment options include conservative or endoscopic therapy, internal biliary bypass procedures, and liver transplantation in carefully selected cases. Surgical resection has been used successfully in patients with monolobar disease. An orthotopic liver transplant is another option, used only when antibiotics have no effect, in combination with recurring cholangitis. With a liver transplant, cholangiocarcinoma is usually avoided in the long run.

Family studies are necessary to determine if Caroli disease is due to inheritable causes. Regular follow-ups, including ultrasounds and liver biopsies, are performed.

Treatment may include the following:

- Surgery with or without radiation

- Radiotherapy

Fast neutron therapy has been used successfully to treat salivary gland tumors, and has shown to be significantly more effective than photons in studies treating unresectable salivary gland tumors.

- Chemotherapy

Initial treatment is supportive, with the use of agents to treat cholestasis and pruritus, including the following:

- Ursodeoxycholic acid

- Cholestyramine

- Rifampin

- Naloxone, in refractory cases

The partial external biliary diversion (PEBD) procedure is a surgical approach that diverts bile from the gallbladder externally into an ileostomy bag.

Patients should be supplemented with fat-soluble vitamins, and occasionally medium-chain triglycerides in order to improve growth.

When liver synthetic dysfunction is significant, patients should be listed for transplantation. Family members should be tested for PFIC mutations, in order to determine risk of transmission.

Because of their location, these tumors tend to become symptomatic late in their development and therefore are not usually resectable at the time of presentation. This is variable as, due to obstruction, jaundice may present early and compel the patient to seek help. Complete resection of the tumor offers hope of long-term survival, and of late there has been renewed interest in liver transplantation from deceased donors along with add on therapy. Prognosis remains poor.

Extrahepatic cholestasis can usually be treated by surgery.

Pruritis in cholestatic jaundice is treated by Antihistamines, Ursodeoxycholic Acid, Phenobarbital

Simple cholecystectomy is suitable for type I patients. For types II–IV, subtotal cholecystectomy can be performed to avoid damage to the main bile ducts. Cholecystectomy and bilioenteric anastomosis may be required. Roux-en-Y hepaticojejunostomy has shown good outcome in some studies.

Small carcinoids (<2 cm) without features of malignancy may be treated by appendectomy if complete removal is possible. Other carcinoids and adenocarcinomas may require right hemicolectomy. Note: the term "carcinoids" is outdated: these tumors are now more accurately called "neuroendocrine tumors." For more information, see "appendiceal neuroendocrine tumors."

Pseudomyxoma peritonei treatment includes cytoreductive surgery which includes the removal of visible tumor and affected essential organs within the abdomen and pelvis. The peritoneal cavity is infused with heated chemotherapy known as HIPEC in an attempt to eradicate residual disease. The surgery may or may not be preceded or followed with intravenous chemotherapy or HIPEC.

AIP often completely resolves with steroid treatment. The failure to differentiate AIP from malignancy may lead to unnecessary pancreatic resection, and the characteristic lymphoplasmacytic infiltrate of AIP has been found in up to 23% of patients undergoing pancreatic resection for suspected malignancy who are ultimately found to have benign disease. In this subset of patients, a trial of steroid therapy may have prevented a Whipple procedure or complete pancreatectomy for a benign disease which responds well to medical therapy. "This benign disease resembles pancreatic carcinoma both clinically and radiographically. The diagnosis of autoimmune pancreatitis is challenging to make. However, accurate and timely diagnosis may preempt the misdiagnosis of cancer and decrease the number of unnecessary pancreatic resections." Autoimmune pancreatitis responds dramatically to corticosteroid treatment.

If relapse occurs after corticosteroid treatment or corticosteroid treatment is not tolerated, immunomodulators may be used. Immunomodulators such as azathioprine, and 6-mercaptopurine have been shown to extend remission of autoimmune pancreatitis after corticosteroid treatment. If corticosteroid and immunomodulator treatments are not sufficient, rituximab may also be used. Rituximab has been shown to induce and maintain remission.

Cholesterol gallstones can sometimes be dissolved with ursodeoxycholic acid taken by mouth, but it may be necessary for the person to take this medication for years. Gallstones may recur, however, once the drug is stopped. Obstruction of the common bile duct with gallstones can sometimes be relieved by endoscopic retrograde sphincterotomy (ERS) following endoscopic retrograde cholangiopancreatography (ERCP). Gallstones can be broken up using a procedure called extracorporeal shock wave lithotripsy (often simply called "lithotripsy"), which is a method of concentrating ultrasonic shock waves onto the stones to break them into tiny pieces. They are then passed safely in the feces. However, this form of treatment is suitable only when there is a small number of gallstones.

Laparoscopic cholecystectomy has been used to treat the condition when due to dyskinesia of the gallbladder.

Symptoms may persist after cholecystectomy, and have been linked to the use of proton pump inhibitors.

Osteopathic treatment, oral magnesium supplementation with 325 mg and the use of digestive enzymes caused improvement in one case.

Treatment involves an operation called a choledocholithotomy, which is the removal of the gallstone from the bile duct using ERCP, although surgeons are now increasingly using laparoscopy with cholangiography. In this procedure, tiny incisions are made in the abdomen and then in the cystic duct that connects the gallbladder to the bile duct, and a thin tube is introduced to perform a cholangiography. If stones are identified, the surgeon inserts a tube with an inflatable balloon to widen the duct and the stones are usually removed using either a balloon or tiny basket.

If laparoscopy is unsuccessful, an open choledocholithotomy is performed. This procedure may be used in the case of large stones, when the duct anatomy is complex, during or after some gallbladder operations when stones are detected, or when ERCP or laparoscopic procedures are not available.

Typically, the gallbladder is then removed, an operation called cholecystectomy, to prevent a future occurrence of common bile duct obstruction or other complications.

Treatment of hepatomegaly will vary depending on the cause of the liver enlargement and hence accurate diagnosis is the primary concern. In the case of auto-immune liver disease, prednisone and azathioprine may be used for treatment.

In the case of lymphoma the treatment options include single-agent (or multi-agent) chemotherapy and regional radiotherapy, also surgery may be an option in specific situations.Meningococcal group C conjugate vaccine are also used in some cases.

In primary biliary cirrhosis ursodeoxycholic acid helps the bloodstream remove bile which may increase survival in some affected individuals.

Cholecystectomy (gallbladder removal) has a 99% chance of eliminating the recurrence of cholelithiasis. Surgery is only indicated in symptomatic patients. The lack of a gallbladder may have no negative consequences in many people. However, there is a portion of the population—between 10 and 15%—who develop a condition called postcholecystectomy syndrome which may cause gastrointestinal distress and persistent pain in the upper-right abdomen, as well as a 10% risk of developing chronic diarrhea.

There are two surgical options for cholecystectomy:

- Open cholecystectomy is performed via an abdominal incision (laparotomy) below the lower right ribs. Recovery typically requires 3–5 days of hospitalization, with a return to normal diet a week after release and to normal activity several weeks after release.

- Laparoscopic cholecystectomy, introduced in the 1980s, is performed via three to four small puncture holes for a camera and instruments. Post-operative care typically includes a same-day release or a one night hospital stay, followed by a few days of home rest and pain medication. Laparoscopic cholecystectomy patients can, in general, resume normal diet and light activity a week after release, with some decreased energy level and minor residual pain continuing for a month or two. Studies have shown that this procedure is as effective as the more invasive open cholecystectomy, provided the stones are accurately located by cholangiogram prior to the procedure so that they can all be removed.

Cholangitis requires admission to hospital. Intravenous fluids are administered, especially if the blood pressure is low, and antibiotics are commenced. Empirical treatment with broad-spectrum antibiotics is usually necessary until it is known for certain which pathogen is causing the infection, and to which antibiotics it is sensitive. Combinations of penicillins and aminoglycosides are widely used, although ciprofloxacin has been shown to be effective in most cases, and may be preferred to aminoglycosides because of fewer side effects. Metronidazole is often added to specifically treat the anaerobic pathogens, especially in those who are very ill or at risk of anaerobic infections. Antibiotics are continued for 7–10 days. Drugs that increase the blood pressure (vasopressors) may also be required to counter the low blood pressure.