Background: Recent studies show depression as a predictor of morbidity and mortality in patients after myocardial infarction (MI) and treating depression does not improve their survival. Not all depressed patients respond adequately to treatment. Treatment-resistant-depression (TRD) may be the reason why previous studies did not demonstrated survival benefits in treated depressed post-MIs. Purpose: To examine depression severity (DS) and progressively worsening depression symptoms (PWDS) contributions to morbidity and mortality of depressed post-MIs. It compared mortality rates between TRD and treatment responsive depression in depressed post-MIs independent of biosocial predictors. Methods: A secondary data analysis using data from the 1834 depressed post-MIs in the Enhancing Recovery in Coronary Heart Disease (ENRICHD) trial, which included 770 patients who were treated for depression. The TRD, as<50% reduction in HAM-D score from baseline to 6 months and a total HAM-D score>10 at 6 months, occurred in 13.4% (n=103) of the depressed post-MIs who were treated. Cox regression analyses were used to examine the independent contributions of DS, PWDS, and TRD to morbidity and mortality after controlling for the biosocial predictors. Results: Depression severity was associated with increased risk of mortality for men, not women (HRs: male low severity=1; male high severity=1.42; female low severity=1.80; female high severity=1.61). The PWDS predicted mortality, depending on minority status after controlling for biosocial factors. Among depressed post-MIs, PWDS was associated with increased risk of mortality, greater in minorities than in whites (HRs: white no progression=1; white worsening=2.83; minority no progression=0.71; minority worsening=8.20). The DS (HR=1.013) and PWDS (HR=1.026) were significant independent predictors of morbidity. TRD significantly predicted mortality (HR=2.783) among the treated depressed post-MIs. Conclusion: This study demonstrated that DS and PWDS are independent contributors to the risk of mortality and morbidity in depressed post-MIs. TRD is also associated with increased mortality in treated depressed patients. It is important to continue to monitor depression among treated post-MIs. Since, TRD post-MIs are at higher risk for mortality, closer follow-up and more aggressive risk factor modification needed to improve cardiac outcomes. This may lead to an integrated treatment strategy that may decrease risk of morbidity and mortality in post-MIs.