Early detection of the disease is important, since physical and neurological damage may be irreversible even if cured. Medications can decrease the risk of those living with people with leprosy from acquiring the disease and likely those with whom people with leprosy come into contact outside the home. However, concerns are known of resistance, cost, and disclosure of a person's infection status when doing follow-up of contacts. Therefore, the WHO recommends that people who live in the same household be examined for leprosy and be treated only if symptoms are present.

The Bacillus Calmette–Guérin (BCG) vaccine offers a variable amount of protection against leprosy in addition to tuberculosis. It appears to be 26 to 41% effective (based on controlled trials) and about 60% effective based on observational studies with two doses possibly working better than one. Development of a more effective vaccine is ongoing.

Several different approaches for classifying leprosy exist, but parallels exist.

- The World Health Organization system distinguishes "paucibacillary" and "multibacillary" based upon the proliferation of bacteria.("-" refers to a low quantity.)

- The SHAY scale provides five gradations.

- The ICD-10, though developed by the WHO, uses Ridley-Jopling and not the WHO system. It also adds an indeterminate ("I") entry.

- In MeSH, three groupings are used.

A difference in immune response to the tuberculoid and lepromatous forms is seen.

Leprosy may also be divided into:

This disease may also occur with only neural involvement, without skin lesions.

The condition should be distinguished from:

- Basal cell carcinoma

- Sarcoidosis

- Discoid lupus erythomatosus

- Leprosy

- Deep fungal infection

A dermatologist or general physician usually administers combination therapy of drugs used for tuberculosis, such as Rifampicin, Isoniazid and Pyrazinamide (possibly with either streptomycin or ethambutol).

Lucio's phenomenon is treated by anti-leprosy therapy (dapsone, rifampin, and clofazimine), optimal wound care, and treatment for bacteremia including antibiotics. In severe cases exchange transfusion may be helpful.

Borderline tuberculoid leprosy is a cutaneous condition similar to tuberculoid leprosy except the skin lesions are smaller and more numerous.

Erythema nodosum is diagnosed clinically. A biopsy can be taken and examined microscopically to confirm an uncertain diagnosis. Microscopic examination usually reveals a neutrophilic infiltrate surrounding capillaries that results in septal thickening, with fibrotic changes in the fat around blood vessels. A characteristic microscopic finding is radial granulomas, well-defined nodular aggregates of histiocytes surrounding a stellate cleft.

Additional evaluation should be performed to determine the underlying cause of erythema nodosum. This may include a full blood count, erythrocyte sedimentation rate (ESR), antistreptolysin-O (ASO) titer and throat culture, urinalysis, intradermal tuberculin test, and a chest x-ray. The ESR is typically high, the C-reactive protein elevated, and the blood showing an increase in white blood cells.

The ESR is initially very high, and falls as the nodules of erythema nodosum. The ASO titer is high in cases associated with a streptococcal throat infection. A chest X-ray should be performed to rule out pulmonary diseases, in particular sarcoidosis and Löfgren syndrome.

Lepromatous leprosy is a form of leprosy characterized by pale macules in the skin.

It results from the failure of Th1 cell activation which is necessary to eradicate the mycobacteria (Th1 response is required to activate macrophages that engulf and contain the disease). In lepromatous leprosy, TH2 response is turned on, and because of reciprocal inhibition (IL-4; IL-10), the cell-mediated response (TH1) is depressed.

This debilitating form of leprosy begins to spread causing the eyebrows to disappear and spongy tumor like swellings appear on the face and body. The disease attacks the internal organs, bones, joints and marrow of the body resulting in physical degeneration. The result is deformity with loss of feeling in the fingers and toes which eventually fall off. Contrary to popular belief, both forms of leprosy are curable, with the lepromatous form classically treated with antibiotics Dapsone, Rifampin and Clofazimine for as long as 2–5 years, but if left untreated the person may die up to 20 or 30 years from its inception.

Early detection of the disease is of utmost importance, since severe physical and neurological damage are irreversible even if cured (e.g. blindness, loss of digits/limbs/sensation). Early infection is characterized by a well demarcated, usually pale, skin lesion which has lost its hair, and there may be many of these lesions if the infection is more severe (most commonly found on the cooler parts of the body such as the elbows, knees, fingers, or scrotum, as the bacteria thrive in cooler environments). This early presentation is the same for both tuberculous and lepromatous forms of leprosy as they are a spectrum of the same disease (lepromatous being the more contagious and severe form in patients with impaired Th1 response). Disease progression is extremely slow, and signs of infection may not appear for years.

Family members, and especially children, who have family members with the disease are most at risk. The disease is believed to be spread through respiratory droplets in close quarters like its relative Mycobacterium tuberculosis, and similarly requires extended exposure to an individual in most situations, so outsiders and healthcare workers are normally not infected (except with the most infective individuals such as those in the most progressed lepromatous forms, as those patients have the highest bacterial loads).

Histoid leprosy is a skin condition, a rare form of multibacillary leprosy.

The differential diagnosis for podoconiosis includes other causes of tropical lymphedema, such as filariasis or leprosy, and mycetoma pedis. Podoconiosis begins almost exclusively in the foot, as opposed to filariasis, where the initial edema can appear anywhere in the lower extremities. Podoconiosis is usually asymmetrically bilateral, whereas filariasis and mycetoma are usually unilateral. Additionally, groin involvement with podoconiosis is extremely rare and is usually indicative of filariasis.

If a clinical distinction between podoconiosis and filariasis cannot be made based on history and examination alone, blood smears and ELISA antigen testing can be useful to screen for filariasis.

The disfigurement associated with podoconiosis can include soft or firm edema, and in later stages firm nodules and a mossy appearance, whereas mycetoma is characterized by firm nodules and edema, usually without the mossy appearance of podoconiosis. Additionally, the edema of podoconiosis is typically more striking and extends more proximally than the edema of mycetoma. Radiology can help distinguish between podoconiosis and mycetoma if the diagnosis is questionable.

Local epidemiology can also be a clue to diagnosis, as podoconiosis is typically found in higher altitude areas with volcanic soils, whereas mycetoma is found along the "mycetoma belt" between latitudes 15 south and 30 north, and filariasis is uncommon at higher altitudes and other environments in which the mosquito vector is less prevalent.

Podoconiosis can be distinguished from leprosy by the preservation of sensation in the affected limb and the isolation of disease to the lower extremities.

The cornerstone of prevention and treatment of podoconiosis is avoidance of exposure to irritant soils. Wearing shoes in the presence of irritant soils is the primary method of exposure reduction. In Rwanda, a country of high disease prevalence, the government has banned walking barefoot in public, in order to curtail podoconiosis and other soil-borne diseases.

Once the disease has developed, rigorous foot hygiene including daily washing with soap and water, application of an emollient, and nightly elevation of the affected extremity has been shown to reduce swelling and disability. Compression wrapping and decongestive physiotherapy of the affected extremity has been shown to be effective in other forms of lymphedema, but the benefits of these therapies have not been rigorously studied in podoconiosis. Nodules will not resolve with these conservative measures, although surgical removal of the nodules can be performed.

It is not lethal in nature and is responsive to tetracycline or ciprofloxacin. Surgical treatment include rhinoplasty. However, if left untreated the disease can lead to sepsis, bleeding, or other chronic conditions that can be fatal.

A positive culture in MacConkey agar is diagnostic, but cultures are only positive in 50–60% of cases. Diagnostic characteristics are most commonly found in the granulomatous stage and are described as being chronic inflammatory cells, Russell bodies, and pseudoepitheliomatous hyperplasia, and groups of large vacuolated histiocytes containing "Klebsiella rhinoscleromatis" (Mikulicz cells).

The diffuse leprosy of Lucio and Latapí, also known as diffuse lepromatous leprosy or "pretty leprosy" is a clinical variety of lepromatous leprosy. It was first described by Lucio and Alvarado in 1852 and re-identified by Latapí in 1936. It is common in Mexico (23% leprosy cases) and in Costa Rica and very rare in other countries.

Borderline lepromatous leprosy is a skin condition with numerous, symmetrical skin lesions.

Granuloma multiforme (also known as "Mkar disease" and "granuloma multiforme (Leiker)") is a cutaneous condition most commonly seen in central Africa, and rarely elsewhere, characterized by skin lesions that are on the upper trunk and arms in sun-exposed areas. It may be confused with tuberculoid leprosy, with which it has clinical similarities. The condition was first noted by Gosset in the 1940s, but it was not until 1964 that Leiker coined the term to describe "a disease resembling leprosy" in his study in Nigeria.

An individual may only develop signs of an infection after a period of subclinical infection, a duration that is called the incubation period. This is the case, for example, for subclinical sexually transmitted diseases such as AIDS and genital warts. Individuals with such subclinical infections, and those that never develop overt illness, creates a reserve of individuals that can transmit an infectious agent to infect other individuals. Because such cases of infections do not come to clinical attention, health statistics can often fail to measure the true prevalence of an infection in a population, and this prevents the accurate modeling of its infectious transmission.

The granulomas of tuberculosis tend to contain necrosis ("caseating tubercules"), but non-necrotizing granulomas may also be present. Multinucleated giant cells with nuclei arranged like a horseshoe (Langhans giant cell) and foreign body giant cells are often present, but are not specific for tuberculosis. A definitive diagnosis of tuberculosis requires identification of the causative organism by microbiologic cultures.

A subclinical infection (sometimes called a preinfection) is an infection that, being , is nearly or completely asymptomatic (no signs or symptoms). A subclinically infected person is thus an asymptomatic carrier of a microbe, intestinal parasite, or virus that usually is a pathogen causing illness, at least in some individuals. Many pathogens spread by being silently carried in this way by some of their host population. Such infections occur both in humans and nonhuman animals. An example of an asymptomatic infection is a mild common cold that is not noticed by the infected individual. Since subclinical infections often occur without eventual overt sign, their existence is only identified by microbiological culture or DNA techniques such as polymerase chain reaction.

Erythema nodosum is self-limiting and usually resolves itself within 3–6 weeks. A recurring form does exist, and in children it is attributed to repeated infections with streptococcus. Treatment should focus on the underlying cause. Symptoms can be treated with bedrest, leg elevation, compressive bandages, wet dressings, and nonsteroidal anti-inflammatory agents (NSAIDs). NSAIDs are usually more effective at the onset of EN versus with chronic disease.

Potassium iodide can be used for persistent lesions whose cause remains unknown. Corticosteroids and colchicine can be used in severe refractory cases. Thalidomide has been used successfully in the treatment of Erythema nodosum leprosum, and it was approved by the U.S. FDA for this use in July 1998.

Aspiration pneumonia is typically caused by aspiration of bacteria from the oral cavity into the lungs, and does not result in the formation of granulomas. However, granulomas may form when food particles or other particulate substances like pill fragments are aspirated into the lungs. Patients typically aspirate food because they have esophageal, gastric or neurologic problems. Intake of drugs that depress neurologic function may also lead to aspiration. The resultant granulomas are typically found around the airways (bronchioles) and are often accompanied by foreign-body-type multinucleated giant cells, acute inflammation or organizing pneumonia. The finding of food particles in lung biopsies is diagnostic.

Surgical excision or cryosurgery is the treatment of choice. Treatment with antifungals has been considered ineffective, but the use of clofazimine and dapsone in patients with leprosy and lobomycosis has been found to improve the latter. This treatment regimen, with concomitant itraconazole, has been used to prevent recurrence after surgery.

Diagnosis is clinical. Sensation is tested using graded monofilament.

Ichthyosis acquisita (or "acquired ichthyosis") is a disorder clinically and histologically similar to ichthyosis vulgaris.

The disease is often misdiagnosed as "Blastomyces dermatitidis" or "Paracoccidiodes brasiliensis" due to its similar morphology.