Because human leukocyte antigen (HLA) associations with various infectious diseases have recently been reported, we examined the role of HLA class I alleles in the development of progressive multifocal leukoencephalopathy (PML) or its outcome in 152 patients, including 123 Caucasians and 29 African Americans. Compared to a human immunodeficiency virus positive (HIV+) control population, we observed decreased frequency of HLA-A3 (P = 0.03) in the Caucasian PML group, whereas B18 (P = 0.02), was more frequent. No such difference was found among African American PML patients. We then sought to characterize differences in HLA between PML progressors, whose survival doesn't exceed 1 year, and survivors. Caucasian survivors were less likely to harbor A68 (P = 0.01), whereas African American survivors less frequently displayed Cw4 (P = .01). However, none of these differences reached statistical significance after Bonferroni correction for multiple testing. Further investigations are needed to assess the role of genetics in the incidence of PML or its outcome. Physicians may exercise caution in the use of immunomodulatory medications in patients whose genetic background is associated with an increased risk of PML.