Objective:To assess the impact of opportunistic diseases on survival in patients with HIV disease.Methods:A cohort of 2081 patients followed for a mean of 30 months was studied. Time-dependent Cox proportional hazards analyses were performed using incident opportunistic diseases and CD4 cell counts as independent variables.Results:During follow-up, 730 (35%) patients died. The occurrence ofPneumocystis cariniipneumonia (PCP), cytomegalovirus (CMV) disease,Mycobacterium aviumcomplex (MAC) disease,Candidaesophagitis, Kaposi's sarcoma, lymphoma, progressive multifocal leukoencephalopathy (PML), dementia, wasting, toxoplasmosis, and cryptosporidiosis were all significantly associated with death, independently of CD4 cell count (allP< 0.001 for opportunistic diseases controlling for CD4 cell count). The magnitude of increased risk was greatest for lymphoma [relative hazard (RH), 7.2], PML (RH, 3.9), MAC (RH, 3.0) and CMV (RH, 2.2). Cryptococcosis (RH, 0.94) and herpes zoster (RH, 0.85) were not associated with death. In a multivariate Cox proportional hazards analysis, MAC [RH, 2.56; 95% confidence interval (CI), 2.1–3.1], CMV (RH, 1.63; 95% CI, 1.3–2.1), toxoplasmosis (RH, 1.85; 95% CI, 1.3–2.6), PCP (RH, 1.29; 95% CI, 1.1–1.5), and CD4 cell count were significantly associated with death. Patients who had opportunistic diseases had significantly greatly monthly declines in CD4 counts (−11 × 106/l per month) than those who did not (−6 × 106/l per month;P< 0.001).Conclusion:Most opportunistic diseases increase the risk of death independently of CD4 cell count. These data support the hypothesis that opportunistic diseases enhance HIV pathogenesis and further underscore the importance of prophylaxis.