A group of 10 leukocyte and lymphocyte subsets were measured by simultaneous dual immunofluorescence and flow cytometry in a group of homosexual men from the San Francisco General cohort. Absolute numbers and percentages of lymphocytes were determined in 30 individuals who progressed to AIDS and 29 who did not over a 44-month period at annual intervals. At entry into the study, all subjects were asymptomatic, HIV seropositive, and had multiple changes in lymphocyte subsets compared to HIV-negative controls. In progressors, large changes occurred from the first visit to the last visit before progression in both absolute numbers and percentages of CD4 cells. The percentage of HLA-DR-bearing CD8 cells also increased. We utilized a proportional hazards model to assign a predictive value for progression to AIDS to lymphocyte subsets in both univariate and multivariate tests. Increased DR-positive CD8 cells, decreased CD4 cells, and increased CD8-positive, Leu 7-positive cells independently predicted progression to AIDS at P less than 0.006 (relative hazard 5.8-4.0). In a multivariate model, the most useful tests were either increased numbers or percentages of DR-positive CD8 cells. These data suggest parsimonious approaches to following HIV-positive individuals and further support the possibility of autoreactive T cells in the pathogenesis of HIV-associated diseases.