ObjectiveWe sought to comprehensively evaluate predictors of poststroke depression (PSD) in the United States and to compare PSD to post–myocardial infarction (MI) depression to determine whether ischemic stroke uniquely elevates risk of depression.MethodsThis is a retrospective cohort study of 100% deidentified inpatient, outpatient, and subacute nursing Medicare data from 2016 to 2017 for US patients ≥65 years of age from July 1, 2016, to December 31, 2017. We calculated Kaplan-Meier unadjusted cumulative risk of depression up to 1.5 years after the index admission. We performed Cox regression to report the hazard ratio for diagnosis of depression up to 1.5 years after stroke vs MI and independent predictors of PSD, and we controlled for patient demographics, comorbid conditions, length of stay, and acute stroke interventions.ResultsIn fully adjusted models, patients with stroke (n = 174,901) were ≈50% more likely than patients with MI (n = 193,418) to develop depression during the 1.5-year follow-up period (Kaplan-Meier cumulative risk 0.1596 ± 0.001 in patients with stroke vs 0.0973 ± 0.000778 in patients with MI, log-rank p < 0.0001). History of anxiety was the strongest predictor of PSD, while discharge home was most protective. Female patients, White patients, and patients <75 years of age were more likely to be diagnosed with depression after stroke.ConclusionsDespite the similarities between MI and stroke, patients with stroke were significantly more likely to develop depression. There were several predictors of PSD, most significantly history of anxiety. Our findings lend credibility to a stroke-specific process causing depression and highlight the need for consistent depression screening in all patients with stroke.