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To define predictors of survival time in late human immunodeficiency virus type 1 (HIV-1) disease, long- and short-duration survivors were studied after their CD4⁺ T cells fell to ⩽50/mm³. Immune activation of CD4⁺ and CD8⁺ T cells, as measured by elevated cell surface expression of CD38 antigen, was strongly associated with shorter subsequent survival (P ⩾ .002). The naive CD45RA⁺CD62L⁺ T cell reserve was low in all subjects and did not predict survival (P = .34 for .34⁺ and .08 for CD8⁺ cells). Higher virus burden correlated with CD8⁺ but not CD4⁺ cell activation and, after correcting for multiple comparisons, was not associated with shorter survival (P = .02). All of the patients' viruses used CCR5, CXCR4, or both, and coreceptor usage did not predict survival (P = .27). Through mechanisms apparently unrelated to higher virus burden, immune activation is a major determinant of survival in advanced …