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Background: HIV infection (HIV+) and major depressive disorder (MDD) are each associated with an increased risk of ischemic stroke. While depressive disorders are common among HIV+ people, it is not known if MDD is a risk factor for ischemic stroke in the HIV population.Methods and Results: We analyzed data on 106,363 (33,544 HIV+; 72,819 HIV-) participants who were free of baseline cardiovascular disease from the Veterans Aging Cohort Study, an observational cohort of HIV+ and matched uninfected veterans in care from April 1st, 2003 through September 30, 2012. International Classification of Diseases, Ninth Revision codes from medical records were used to determine baseline MDD and the primary outcome, incident ischemic stroke. The prevalence of MDD was similar for HIV+ and HIV- veterans (20.0% and 18.8%, respectively). After a median of 9.2 years of follow-up, stroke rates per 1000 person-years were highest among HIV+/MDD+ veterans (5.8; 95% CI:5.2-6.5), followed by HIV+/MDD- veterans (5.3; 95% CI:5.0-5.6), HIV-/MDD+ (5.1; 95% CI: 4.7-5.5), and HIV-/MDD- (4.8; 95% CI: 4.6-5.0). In Cox proportional hazard models, MDD was associated with an increased risk of ischemic stroke for both HIV+ and HIV- veterans, even after adjusting for sociodemographic adjusting for sociodemographic characteristics and cerebrovascular risk factors (Table). The risk persisted among HIV+ people after further adjusting for HIV factors (Table). These associations were modestly attenuated with the addition of cocaine and alcohol abuse/dependence.Conclusions: In the VACS, MDD was associated with an increased risk of ischemic stroke in HIV+ veterans after adjustment for sociodemographic characteristics, traditional cerebrovascular risk factors, and HIV factors; however, this association was modestly attenuated after adjustment for cocaine and alcohol abuse/dependence. Future research is necessary to: (a) fully elucidate the relationships among MDD, cocaine/alcohol use, and stroke risk and (b) determine whether intervening on MDD reduces stroke risk in HIV+ and HIV- people. Clinical providers should be aware of the increased stroke risk among HIV+ adults with MDD.