© 2015 American Heart Association, Inc. Depression and stress have each been found to be associated with poor prognosis in patients with coronary heart disease. A recently offered psychosocial perfect storm conceptual model hypothesizes amplified risk will occur in those with concurrent stress and depressive symptoms. We tested this hypothesis in a large sample of US adults with coronary heart disease. Methods and Results-Participants included 4487 adults with coronary heart disease from the REasons for Geographic and Racial Differences in Stroke study, a prospective cohort study of 30 239 black and white adults. We conducted Cox proportional hazards regression with the composite outcome of myocardial infarction or death and adjustment for demographic, clinical, and behavioral factors. Overall, 6.1% reported concurrent high stress and high depressive symptoms at baseline. During a median 5.95 years of follow-up, 1337 events occurred. In the first 2.5 years of followup, participants with concurrent high stress and high depressive symptoms had increased risk for myocardial infarction or death (adjusted hazard ratio, 1.48 [95% confidence interval, 1.08-2.02]) relative to those with low stress and low depressive symptoms. Those with low stress and high depressive symptoms (hazard ratio, 0.92 [95% confidence interval, 0.66-1.28]) or high stress and low depressive symptoms (hazard ratio, 0.86 [95% confidence interval, 0.57-1.29]) were not at increased risk. The association on myocardial infarction or death was not significant after the initial 2.5 years of follow-up (hazard ratio, 0.89 [95% confidence interval, 0.65-1.22]). Conclusions-Our results provide initial support for a psychosocial perfect storm conceptual model; the confluence of depressive symptoms and stress on medical prognosis in adults with coronary heart disease may be particularly destructive in the shorter term.