The exact immune defects leading to human immunodeficiency virus (HIV)-associated opportunistic infections, malignancies, and death are unknown. In this study, the relationship between survival and 2 immune functions, cytomegalovirus-specific antibody-dependent cellular cytotoxicity (ADCC) and natural killer (NK) activity, was determined by using peripheral blood mononuclear cells from 39 severely immunocompromised patients (median CD4 count, 7). Median follow-up was 414 days; 15 subjects died and 24 remained alive. In a Kaplan-Meier analysis, high baseline ADCC (>median) was associated with improved survival (P = .05). A similar trend was observed for NK activity (P = .1). In a multivariate model controlling for baseline CD4 cell count, HIV RNA, and use of protease inhibitors during follow-up, high ADCC, but not high NK activity, remained significantly associated with a lower risk of death (relative risk, 0.18; 95% confidence interval, 0.05–0.75). ADCC may be an important determinant of disease progression independently of anti-retroviral therapy, CD4 cell count, and HIV RNA.