OBJECTIVE: To investigate the relationship of cerebrovascular risk factors (CVRFs), endothelial function, carotid artery intima medial thickness (IMT), and neuropsychological performance in a sample of 198 middle-aged and older individuals with major depressive disorder (MDD). Neuropsychological deficits are common among adults with MDD, particularly among those with CVRFs and potentially persons with subclinical vascular disease. METHODS: CVRFs were indexed by the Framingham Stroke Risk Profile (FSRP) and serum cholesterol levels obtained by medical history and physical examination. Patients completed a neuropsychological test battery including measures of executive functioning, working memory, and verbal recall. Vascular function was indexed by carotid artery IMT and brachial artery flow mediated dilation (FMD). Hierarchical multiple regression analyses were used to investigate the association between CVRFs, vascular disease, and neurocognitive performance. RESULTS: Greater FSRP scores were associated with poorer executive functioning (b = -0.86; p = .041) and working memory (b = -0.90; p = .024). Lower high-density lipoprotein levels also were associated with poorer executive functioning (b = 1.03; p = .035). Higher IMT (b = -0.83; p = .028) and lower FMD (b = 1.29; p = .032) were associated with poorer executive functioning after controlling for CVRFs. Lower FMD was also associated with poorer working memory (b = 1.58; p = .015). CONCLUSIONS: Greater CVRFs were associated with poorer neuropsychological performance. Vascular dysfunction also was associated with neuropsychological decrements independent of traditional CVRFs.