To examine factors affecting survival after diagnosis of progressive multifocal leukoencephalopathy (PML), we analyzed data from an observational cohort study, the Adult and Adolescent Spectrum of HIV Disease project. We identified 415 patients diagnosed with PML during 1990–1997. The median survival time after diagnosis was 1 month. By use of an extended proportional hazards, multivariate regression model, risk factors associated with decreased survival time included CD4 count 9 cells/L (risk ratio [RR], 2.1; 95% confidence interval [CI], 1.3–3.5) compared with ⩾0.20 × 109 cells/L, whereas factors associated with increased survival time were prescription of antiretroviral medication that contained a protease inhibitor (RR, 0.2; 95% CI, 0.1–0.4) and prescription of other antiretroviral medication (RR, 0.6; 95% CI, 0.5–0.8) compared with no antiretroviral prescription. We conclude that protease inhibitor use (in combination antiretroviral therapy) is likely to favorably affect survival time after diagnosis of PML.