Smoking is a potential risk factor for age-related cognitive decline. To date, no study has examined the association between smoking and cognitive decline in men living with human immunodeficiency virus (HIV). The aim of this present study is to examine whether smoking status and severity in midlife is associated with a rate of decline in cognitive processing speed among older HIV-seropositive and HIV-seronegative men who have sex with men. Data from 591 older HIV-seropositive and HIV-seronegative men who have sex with men from the Multicenter AIDS Cohort Study were examined. All participants had information on smoking history collected before age 50 years and at least 5 years of follow-up after age 50. Smoking history was categorized as never smoker, former smoker, and current smoker and cumulative pack years was calculated. The raw scores of three neuropsychological tests (Trail Making A, Trail Making B, and Symbol Digit Modalities tests) were log transformed (Trail Making A and B) and used in linear mixed models to determine associations between smoking history and at least subsequent 5-year decline in cognitive processing speed. There were no significant differences in the rates of neurological decline among never smokers, former smokers, and current smokers. Findings were similar among HIV-seropositive participants. However, an increase of 5 pack-years was statistically significantly associated with a greater rate of decline in the Trail Making Test B score and Composite Score (beta -0.0250 [95% CI, -0.0095 to -0.0006] and -0.0077 [95% CI, -0.0153 to -0.0002], respectively). We found no significant association between smoking treated as a categorical variable (never smoked, former smoker, or current smoker) and a small change in every increase of 5 pack-years on measures of psychomotor speed and cognitive flexibility. To optimize healthy aging, interventions for smoking cessation should be tailored to men who have sex with men.