Published Online First 13 September 2005 . . . . . . . . . . . . . . . . . . . . . . . S ubstantial prospective, epidemiologic evidence now suggests that among patients admitted to the hospital for an acute coronary syndrome (ACS), those suffering comorbid depression are at significantly increased risk for future cardiovascular morbidity and mortality. This appears to be true even for patients with mild depressive symptoms that do not meet full clinical criteria for major depression. Given the remarkable prevalence of depressive symptoms among patients with coronary disease (approximately 20–30%), the issue is far from trivial. However, why depression is a risk factor for poor prognosis is unclear. In many studies, depression is an independent predictor of poor outcomes, which has prompted several investigators to suggest that depression itself may be causally related to the poor prognosis observed in depressed ACS patients. Other studies have demonstrated that depression is no longer an independent predictor of outcomes when the severity of coronary disease is rigorously measured and adjusted for in the analyses. This has led some to conclude that depression is a marker of disease severity, rather than an independent poor prognostic factor. 9 Adding to the complexity of this debate is that while there are several plausible mechanisms through which depression may mediate worse outcomes, none has been proven to be the link engendering adverse clinical end points. Moreover, it is unknown if treating depression in ACS patients will improve cardiovascular outcomes. Two large trials 12 have examined this issue; only one was powered to detect a reduction in clinical events, and it was a negative study. Yet despite the controversies and uncertainties regarding depression and coronary disease, it is important to not lose focus regarding three concerning facts with respect to ACS patients: (1) depression is common; (2) causal or not, depression portends a worse cardiovascular prognosis; and (3) these patients have a comparatively poorer quality of life.