Vital exhaustion, defined as a combination of fatigue, lack of energy, feelings of hopelessness, loss of libido, and increased irritability, has been proposed as a risk indicator for the development of coronary heart disease (CHD). It is unclear if the association between vital exhaustion and CHD is independent of sleep behavior, depression, and physical activity. We ascertained sense of exhaustion among 5,053 male college alumni who were free of cardiovascular disease, cancer, and chronic obstructive pulmonary disease by asking, "How often do you experience sense of exhaustion (except after exercise)?" on a health survey in 1980. Eight hundred fifteen men died during 12 years of follow-up, 25% due to CHD. After adjustment for age, body mass index, smoking status, and history of physician-diagnosed diabetes and hypertension, frequent sense of exhaustion was associated with a twofold increase in CHD mortality (rate ratio 2.07; 95% confidence interval 1.08 to 3.96). After additional adjustment for insomnia, sleep duration, use of sleeping pills and tranquilizers, physical activity, history of physician-diagnosed depression, and alcohol intake, the rate ratio was not appreciably altered; however, the association now was of borderline significance (rate ratio 2.06; 95% confidence interval: 0.98 to 4.36) because there were only 10 deaths from CHD among men who were frequently exhausted. In a prospective observational study, frequent sense of exhaustion appeared to be independently associated with increased risk of CHD mortality in men.