BACKGROUND Depression is associated with poor adherence to medications and worse prognosis in patients with acute coronary syndrome (ACS). PURPOSE To determine whether cognitive, behavioral, and/or psychosocial vulnerabilities for depression explain the association between depression and medication adherence among ACS patients. METHODS One hundred sixty-nine ACS patients who agreed to have their aspirin adherence measured using an electronic pill bottle for 3 months were enrolled within 1 week of hospitalization. Linear regression was used to determine whether depression vulnerabilities predicted aspirin adherence after adjustment for depressive symptoms, demographics, and comorbidity. RESULTS Of the depression vulnerabilities, only role transitions (beta = -3.32; P = 0.02) and interpersonal conflict (beta -3.78; P = 0.03) predicted poor adherence. Depression vulnerabilities did not mediate the association between depressive symptoms and medication adherence. CONCLUSIONS Key elements of the psychosocial context preceding the ACS including major role transitions and conflict with close contacts place ACS patients at increased risk for poor medication adherence independent of depressive symptoms.