To examine the effect of highly active antiretroviral therapy (HAART) on the occurrence of primary brain lymphoma (PBL), determine the risk factors for PBL, and assess the difference in survival between individuals who did and did not develop PBL, data were analyzed from the Michigan Adult/Adolescent Spectrum of HIV Disease project (ASD). Among 4,026 HIV-infected individuals enrolled in ASD between January 1990 and December 2000, 64 (1.6%) were diagnosed with PBL. The incidence rate of PBL declined from 5.6 cases per 1000 person-year in the pre-HAART era to 2.1 cases per 1000 person-year in post-HAART era. In the multivariate analysis, individuals whose CD4 count at entry in ASD was either <50 cells/microL (OR: 5.0) or 50-200 cells/microL (OR: 2.3) were significantly more likely to develop PBL than those with a CD4 count >/= 200 cells/microL. PBL was a terminal condition in these patients. The median survival time was consistently shorter among individuals who developed PBL than those who did not, regardless of their CD4 count at entry into ASD.