We previously reported that major depression in patients in the hospital after a myocardial infarction (MI) substantially increases the risk of mortality during the first 6 months. We examined the impact of depression over 18 months and present additional evidence concerning potential mechanisms linking depression and mortality. Two-hundred twenty-two patients responded to a modified version of the National Institute of Mental Health Diagnostic Interview Schedule (DIS) for a major depressive episode at approximately 7 days after MI. The Beck Depression Inventory (BDI), which measures depressive symptomatology, was also completed by 218 of the patients. All patients and/or families were contacted at 18 months to determine survival status. Thirty-five patients met the modified DIS criteria for major in-hospital depression after the MI. Sixty-eight had BDI scores > or = 10, indicative of mild to moderate symptoms of depression. There were 21 deaths during the follow-up period, including 19 from cardiac causes. Seven of these deaths occurred among patients who met DIS criteria for depression, and 12 occurred among patients with elevated BDI scores. Multiple logistic regression analyses showed that both the DIS (odds ratio, 3.64; 95% confidence interval [CI], 1.32 to 10.05; P = .012) and elevated BDI scores (odds ratio, 7.82; 95% CI, 2.42 to 25.26; P = .0002) were significantly related to 18-month cardiac mortality. After we controlled for the other significant multivariate predictors of mortality in the data set (previous MI, Killip class, premature ventricular contractions [PVCs] of > or = 10 per hour), the impact of the BDI score remained significant (adjusted odds ratio, 6.64; 95% CI, 1.76 to 25.09; P = .0026). In addition, the interaction of PVCs and BDI score marginally improved the model (P = .094). The interaction showed that deaths were concentrated among depressed patients with PVCs of > or = 10 per hour (odds ratio, 29.1; 95% CI, 6.97 to 122.07; P < .00001). Depression while in the hospital after an MI is a significant predictor of 18-month post-MI cardiac mortality. Depression also significantly improves a risk-stratification model based on traditional post-MI risks, including previous MI, Killip class, and PVCs. Furthermore, the risk associated with depression is greatest among patients with > or = 10 PVCs per hour. This result is compatible with the literature suggesting an arrhythmic mechanism as the link between psychological factors and sudden cardiac death and underscores the importance of developing screening and treatment programs for post-MI depression.