A longer life expectancy and a high prevalence of tobacco smoking among HIV patients have led to an increasing cumulative exposure to tobacco in this community. Clinical recommendations for smoking cessation in HIV patients are mainly based on the body of evidence from the general population plus few available data from HIV cohort studies. The assumption that the pathophysiology of tobacco-related diseases in HIV-infected patients is similar to that in the general population may be questionable. This article reviews the pathophysiological mechanisms underlying health problems attributable to tobacco in HIV patients, and how these mechanisms may interact with those of HIV infection. Tobacco smoking exerts a greater health impact on HIV-infected patients than on uninfected smokers. Components of tobacco smoke and HIV infection induce complex interrelated pathophysiological changes through different pathways, affecting various organ systems with a cumulative or synergistic effect. This review supports the contention that HIV infection may confer an increased susceptibility to the harmful effects of smoking. Tobacco-related harm in the setting of HIV infection is still underestimated. A better understanding of the pathophysiological interaction between tobacco smoking and HIV will help to promote smoking cessation in this specific population.