Background and Objectives:The prevalence of mid-life cardiovascular conditions and risk factors are higher in men than women. Associations between mid-life cardiovascular conditions or risk factors and mid-life cognitive decline has been reported, but few studies have assessed sex differences in these associations.Methods:We included 1,857 participants enrolled in the population-based Mayo Clinic Study of Aging who were aged 50-69 years at baseline. Participants were evaluated every 15 months by a coordinator, neurologic evaluation, and neuropsychological testing. The neuropsychological testing used nine tests to calculate global cognitive and domain-specific (memory, language, executive function, and visuospatial skills) z-scores. Nurse abstractors reviewed participant medical records to determine the presence of cardiovascular conditions (coronary heart disease, arrhythmias, congestive heart failure) and risk factors (hypertension, diabetes, dyslipidemia, obesity, ever smoking). Linear mixed-effect models evaluated the association between baseline cardiovascular conditions or risk factors and global and domain-specific cognitive decline. Multivariable models adjusted for demographics, APOE genotype, depression, and other medical conditions. Interactions between sex and each cardiovascular condition or risk factor were examined, and results were stratified by sex.Results:Overall, 1,465 (70.3%) participants had at least one cardiovascular condition or risk factor; the proportion of men was higher than women (767 (83.4%) vs 698 (74.5%), p<0.0001). Cross-sectionally, coronary heart disease and ever smoking were associated with a lower visuospatial z-score in multivariable models. Longitudinally, several cardiovascular conditions and risk factors were associated with declines in global and/or domain-specific z scores, but not visuospatial z-scores. Most cardiovascular conditions were more strongly associated with cognition among women: coronary heart disease, and other cardiovascular conditions were associated with global cognition decline only in women (all p<0.05). Additionally, diabetes, dyslipidemia, and coronary heart disease were associated with language z-score decline only in women (all p<0.05). However, congestive heart failure was associated with language z-score decline only in men (all p<0.05).Conclusions:Mid-life cardiovascular conditions and risk factors are associated with mid-life cognitive decline. Moreover, specific cardiovascular conditions and risk factors have stronger associations with cognition decline in mid-life for women than men despite the higher prevalence of those conditions in men.