Cynical hostility has been associated with increased cardiovascular morbidity and mortality; yet few studies have investigated this relation in population-based samples, and little is known about underlying mechanisms. This study examined the association between hostility, measured by the eight-item Cynical Distrust Scale, and risk for all-cause and cardiovascular mortality and incident myocardial infarction. Subjects were 2,125 men, ages 42-60 years, from the Kuopio Ischemic Heart Disease Risk Factor Study, a longitudinal study of unestablished and traditional risk factors for ischemic heart disease, mortality, and other outcomes. There were 177 deaths (73 cardiovascular) in 9 years of follow-up. Men with hostility scores in the top quartile were at more than twice the risk of all-cause mortality (relative hazards (RH) 2.30, 95% confidence interval (CI) 1.47-3.59) and cardiovascular mortality (RH 2.70, 95% CI 1.27-5.76), relative to men with scores in the lowest quartile. Among 1,599 men without previous myocardial infarction or angina, high scorers also had an increased risk of myocardial infarction (RH 2.18, 95% CI 1.01-4.70). Biologic and socioeconomic risk factors, social support, and prevalent diseases had minimal impact on these associations, whereas adjustments for the behavioral risk factors of smoking, alcohol consumption, physical activity, and body mass index substantially weakened the relations. Simultaneous risk factor adjustment eliminated the observed associations. Results show that high levels of hostility are associated with increased risk of all-cause and cause-specific mortality and incident myocardial infarction and that these effects are mediated primarily through behavioral risk factors.