Background-Positive affect has been associated with better prognosis in patients with ischemic heart disease, but the underlying mechanisms remain unclear. We examined whether positive affect predicted time to first cardiac-related hospitalization and all-cause mortality, and whether exercise mediated this relationship in patients with established ischemic heart disease. Methods and Results-The sample comprised 607 patients with ischemic heart disease from Holbæk Hospital, Denmark. In 2005, patients completed the Global Mood Scale (GMS) to assess positive affect and a purpose-designed question on exercise. Data on mortality and hospitalization were collected from Danish national registers for the period 2006-2010. Adjusted Cox and logistic regression were used to analyze the mediation model. Because no significant association between positive affect and cardiac-related hospitalization was found, we constructed no mediation model for hospitalization. Importantly, patients with high positive affect had a significantly reduced risk of all-cause mortality (hazard ratio, 0.58; 95% confidence interval, 0.37-0.92; unadjusted analysis) and were more likely to exercise (odds ratio, 1.99; 95% confidence interval, 1.44-2.76; unadjusted analysis; odds ratio, 1.48; 95% confidence interval, 1.03-2.13; adjusted analysis). When controlling for positive affect and other relevant variables, patients engaged in exercise were less likely to die during follow-up (hazard ratio, 0.50; 95% confidence interval, 0.31-0.80; P=0.004). Importantly, exercise acted as a mediator in the relationship between positive affect and mortality. Conclusions-Patients with higher levels of positive affect were more likely to exercise and had a lower risk of dying during 5-year follow-up, with exercise mediating the relationship between positive affect and mortality. Interventions aimed at increasing both positive affect and exercise may have better results with respect to patients' prognosis and psychological well-being than interventions focusing on 1 of these factors alone.