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Cigarette smoking has been associated with impaired immune defenses and an increased risk of certain infectious and neoplastic diseases in HIV-1 seronegative populations. We examined the relationship between cigarette smoking and clinical outcome in a prospective cohort of 3221 HIV-1-seropositive men and women enrolled in the Terry Beirn Community Programs for Clinical Research on AIDS. Differences in clinical outcomes between never, former, and current cigarette smokers were assessed using proportional hazards regression analysis. After adjustment for CD4+ cell count, prior disease progression, use of antiretroviral therapy, and other covariates, there was no difference between current smokers and never smokers in the overall risk of opportunistic diseases [relative hazard (RH) = 1.05; 95% confidence interval (CI) 0.90-1.23; p = 0.52] or death (RH = 1.00; 95% CI 0.86-1.18; p = 0.97). However, current smokers were more likely than never smokers to develop bacterial pneumonia (RH = 1.57; 95% CI 1.14-2.15; p = 0.006), oral candidiasis (RH = 1.37; 95% CI 1.16-1.62; p = 0.0002), and AIDS dementia complex (RH = 1.80; 95% CI 1.11-2.90; p = 0.02). In addition, current smokers were less likely to develop Kaposi's sarcoma (RH = 0.58; 95% CI 0.39-0.88; p = 0.01) and several other non-respiratory tract diseases. If confirmed by other studies, these findings have important clinical implications.