Objective To investigate whether fatigue predicts nonfatal ischemic heart disease (IHD) and all-cause mortality in middle-aged men. Methods The study population consisted of 5216 middle-aged men born in the Copenhagen metropolitan area in 1953. At baseline, men free of angina pectoris and previous IHD were asked if they felt fatigued. Information on IHD diagnosis and all-cause mortality was register based. The Cox proportional hazard model was used to test the association at 4-year follow-up. Results Fatigue was associated with hospitalization for nonfatal IHD (hazard ratio [HR] = 1.98, 95% confidence interval [CI] = 1.09-3.61) and all-cause mortality (HR = 3.99, 95% CI = 2.27-7.02). These associations became nonsignificant in multivariable-adjusted models (HR = 1.57, 95% CI = 0.82-3.01 and HR = 1.90, 95% CI = 0.95-3.80). Imputation of missing data did not modify conclusions. Fatigue was a strong independent predictor of first hospitalization for nonfatal IHD among nonsmoking men (HR = 6.00, 95% CI = 2.00-18.04), and the fatigue-by-smoking status interaction was significant (p = .04). Findings should be interpreted with caution because of the small number of participants with IHD (n = 21, 1.5%). Compared to nonfatigued nonsmokers, both fatigued nonsmokers and fatigued smokers had higher hazard of dying (HR = 4.99, 95% CI = 1.31-19.09 and HR = 3.74, 95% CI = 1.32-10.57, respectively), although the fatigue-by-smoking status interaction was not significant (p = .12). Conclusions Fatigue is a potential risk indicator for IHD and mortality. Further research is needed to establish the role of smoking and other life-style characteristics.