The prognostic value of several immunologic markers were compared in Los Angeles Multicenter AIDS Cohort Study (MACS) participants, most of whom had been infected with HIV for> 8 years. Markers studied included CD4+ cell number, flow cytometric measurements of CD8+ cell expression of CD38 and HLA-DR antigens, and serum markers of immune activation including neopterin, β2-microglobulin, soluble interleukin-2 receptor, soluble CD8, and soluble tumor necrosis factor receptor-α (TNF-α) type II. Cox proportional hazards models indicated that elevated CD38 on CD8, a flow cytometric measurement of CD8+ T-lymphocyte activation, was the most predictive marker of those studied for development of a clinical AIDS diagnosis and death. As compared with the reference group, who had CD38 on CD8< 2470 molecules per CD8+ cell and in whom 4 of 99 developed clinical AIDS within 3 years, participants with CD38 on CD8 between 2470 and 3899, 3900 and 7250, and> 7250 had relative risks (and numbers developing AIDS within 3 years) of 5.0 (15 of 81), 12.3 (24 of 60), and 41.4 (36 of 49), respectively. The strong prognostic value of CD38 on CD8 measurements and the fundamental importance of chronic immune activation in the pathogenesis of HIV disease suggests that this marker might have utility in the clinical management of HIV-infected persons.