Pathologic findings attributed to human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) are described in the spleen in studies that encompassed the years preceding highly active anti-retroviral therapy (HAART). Major findings included white-pulp depletion, hemosiderin deposition, spindle cell proliferations, and perivascular hyalinization. Infectious and malignant infiltrates were commonly noted and characterized. The histopathology of AIDS autopsy spleens since the introduction of protease inhibitors has not been studied. Histologic sections from 168 cases of AIDS spleens examined at autopsy over a 19-year period (1982-2000) were evaluated for significant pathologic findings. Multiple morphologic parameters were recorded, including a graded estimation of white-pulp depletion. Significantly less white-pulp depletion was observed in the 39 HAART-era spleens (1995-2000) compared with the 129 spleens from the 1982-1994 patient group (P =.001). The rates of splenic involvement by atypical mycobacteria and cytomegalovirus were similar to those in the past, although the overall clinical rates of these opportunistic infections were found to be decreased. The annual numbers of AIDS autopsies have decreased, reflecting a nationwide trend of lower autopsy rates. Increased survival with HIV infection and AIDS is now apparent. Protease inhibitors, in conjunction with other contemporary therapies, may have contributed to the preservation of white pulp observed in the HAART patient group.