Cigarette smoking is more common among those with HIV compared with the general population. However, it remains unclear whether smoking alters the natural history of HIV infection or if unique health consequences related to smoking occur in the context of HIV. In this article, we review the literature on the effect of smoking on acquisition of HIV, progression of HIV to AIDS, and mortality. Although there was significant heterogeneity in the study populations evaluated, we found little evidence that cigarette smoking increases the risk for acquiring HIV. Two studies observed that smoking was associated with more rapid CD4 cell count declines, but most data suggest that smoking does not accelerate progression to clinical AIDS. The most consistent finding was an increased risk for respiratory infections in smokers. Although no effect of smoking was seen with AIDS-related mortality, findings related to all-cause mortality were inconclusive. Owing to an increase in chronic non-AIDS outcomes in the post-highly active antiretroviral therapy (HAART) era, smoking is likely an increasingly important contributor to morbidity and mortality in HIV-infected populations. Future investigation of the biological and clinical effects of smoking, and of preventive approaches to reduce the heavy burden among individuals with HIV is warranted.