To explore the respective roles of highly active antiretroviral therapy (HAART) and alpha-interferon in improving survival of patients with AIDS-related PML, we retrospectively analyzed all patients with AIDS and PML who were referred to Johns Hopkins University HIV Neurology Program from 1985 to 2000. For 97 evaluable patients, we compared survival of those who were on HAART (three or more antiretroviral drugs) to those who were not on HAART. The effect of alpha-interferon was also studied. Multivariate analysis showed no difference in survival among patients on none, one, or two forms of antiretrovirals; however, survival was significantly greater for those on HAART. Whereas alpha-interferon use was shown to be associated with longer survival (P < 0.057), this effect was not independent of the effects of HAART. HAART significantly increases survival for patients with PML and AIDS; however, alpha-interferon does not appear to provide additional benefit.