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We examined the relationship among low, moderate, and high levels of hopelessness, all-cause and cause-specific mortality, and incidence of myocardial infarction (MI) and cancer in a population-based sample of middle-aged men. Participants were 2428 men, ages 42 to 60, from the Kuopio Ischemic Heart Disease study, an ongoing longitudinal study of unestablished psychosocial risk factors for ischemic heart disease and other outcomes. In 6 years of follow-up, 174 deaths (87 cardiovascular and 87 noncardiovascular, including 40 cancer deaths and 29 deaths due to violence or injury), 73 incident cancer cases, and 95 incident MI had occurred. Men were rated low, moderate, or high in hopelessness if they scored in the lower, middle or upper one-third of scores on a 2-item hopelessness scale. Age-adjusted Cox proportional hazards models identified a dose-response relationship such that moderately and highly hopeless men were at significantly increased risk of all-cause and cause-specific mortality relative to men with low hopelessness scores. Indeed, highly hopeless men were at more than three-fold increased risk of death from violence or injury compared with the reference group. These relationships were maintained after adjusting for biological, socioeconomic, or behavioral risk factors, perceived health, depression, prevalent disease, or social support. High hopelessness also predicted incident MI, and moderate hopelessness was associated with incident cancer. Our findings indicate that hopelessness is a strong predictor of adverse health outcomes, independent of depression and traditional risk factors. Additional research is needed to examine phenomena that lead to hopelessness.