T-PLL is an extremely rare aggressive disease, and patients are not expected to live normal lifespans. Before the recent introduction of better treatments, such as alemtuzumab, the median survival time was 7.5 months after diagnosis. More recently, some patients have survived five years and more, although the median survival is still low.

About four men are diagnosed with this disease for every three women. Despite its overall rarity, it is also the most common type of mature T cell leukemia.

This disease is rare, with fewer than 1 in 10,000 people being diagnosed with HCL during their lives. Men are four to five times more likely to develop hairy cell leukemia than women. In the United States, the annual incidence is approximately 3 cases per 1,000,000 men each year, and 0.6 cases per 1,000,000 women each year.

Most patients are white males over the age of 50, although it has been diagnosed in at least one teenager. It is less common in people of African and Asian descent compared to people of European descent.

It does not appear to be hereditary, although occasional familial cases that suggest a predisposition have been reported, usually showing a common Human Leukocyte Antigen (HLA) type.

As with many cancers, the cause of hairy cell leukemia is unknown. Exposure to tobacco smoke, ionizing radiation, or industrial chemicals (with the possible exception of diesel) does not appear to increase the risk of developing HCL. Farming and gardening appear to increase the risk of HCL in some studies.

Recent studies have identified somatic BRAF V600E mutations in all patients with the classic form of hairy cell leukemia thus sequenced, but in no patients with the variant form.

The U.S. Institute of Medicine (IOM) announced "sufficient evidence" of an association between exposure to herbicides and later development of chronic B-cell leukemias and lymphomas in general. The IOM report emphasized that neither animal nor human studies indicate an association of herbicides with HCL specifically. However, the IOM extrapolated data from chronic lymphocytic leukemia and non-Hodgkin lymphoma to conclude that HCL and other rare B-cell neoplasms may share this risk factor. As a result of the IOM report, the U.S. Department of Veterans Affairs considers HCL an illness presumed to be a service-related disability (see Agent Orange).

Human T-lymphotropic virus 2 (HTLV-2) has been isolated in a small number of patients with the variant form of HCL. In the 1980s, HTLV-2 was identified in a patient with a T-cell lymphoproliferative disease; this patient later developed hairy cell leukemia (a B cell disease), but HTLV-2 was not found in the hairy cell clones. There is no evidence that HTLV-II causes any sort of hematological malignancy, including HCL.

B-cell prolymphocytic leukemia is a more aggressive, but still treatable, form of leukemia. The malignant B cells are larger than average. The name is commonly abbreviated B-PLL.

It can involve deletions from chromosome 11 and chromosome 13.

It has been suggested that some cases may represent a variant of mantle cell lymphoma.

It has a relatively poor prognosis.

A case has been described as CD20+, CD22+, and CD5-.

It can also be CD5+.

Another case was described as CD45+, CD19+, CD20+, CD5+, HLA-DR+, CD10-, CD23+/-, CD38+ and FMC7-.