Cigarette smoking alters the immune system and may improve cognitive deficits in neuropsychiatric disorders. Smoking prevalence is high in human immunodeficiency virus (HIV)-infected patients; however, its effect on HIV-associated cognitive impairment remains unknown in the era of antiretroviral treatment. The authors examined associations of smoking with viral immune profile and cognitive function in a cohort of HIV-seropositive women. This observational cross-sectional study included 56 women (36 HIV-seropositive and 20 HIV-seronegative) surveyed with a tobacco questionnaire: the Fagerström Test for Nicotine Dependency. Viral immune status was obtained 6 to 12 months before questioned. Neurocognitive testing (NP) assessed verbal memory, frontal/executive function, psychomotor speed, and motor speed. A reference group of HIV-seronegative women was used to calculate standardized z-scores. Cognitive impairment was classified using a modified American Academy of Neurology criteria, adding an asymptomatic group based on NP tests. Statistics included parametric and nonparametric tests. HIV-seropositive women were more likely to report a history of smoking (P = 0.028). Among them, current smoking correlated with higher plasma viral load (P = 0.048), and history of smoking correlated with lower CD4 cell count (P = 0.027). The authors observed no associations between cognitive impairment and either current or past history of smoking and no differences in neurocognitive domain scores between HIV-seropositive and -seronegative women or between those with and without a history of smoking. However, restricting analysis to HIV-seropositives showed a significant better performance on the frontal/executive domain in those with history of smoking. In summary, history of smoking correlated with better frontal/executive cognitive domain performance in HIV-seropositive women and with worse viral immune profile.