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The effect of cigarette smoking on CD4+ T lymphocytes was investigated in the San Francisco Men's Health Study cohort. The cohort was established by probability sampling in 1984 to study infection with HIV. Smoking showed an association with increased CD4+ cell counts in all men but the effect was attenuated in HIV-seropositive men (85 cells/μl difference in median counts, non-smokers compared with smokers) compared with HIV-seronegative men (230 cells/μl difference in median counts). The positive dose response between packs smoked per day and CD4+ counts observed in uninfected men was substantially reduced in infected men (slope 87 versus 27 cells/μl). Analysis of data from HIV seroconverters suggest that smokers' counts fall faster than non-smokers' following infection, and that response to smoking becomes less pronounced soon after infection. This report demonstrates that those who monitor CD4+ cell counts in HIV-infected individuals for clinical and/or research purposes should also consider smoking status.