Although 25% of US men indicate that they are trying to lose weight, the association between intentional weight loss and longevity in men is unknown. The authors analyzed prospective data from 49,337 overweight (initial body mass index > or =27) white men aged 40-64 years who, in 1959-1960, answered questions on weight change direction, amount, time interval, and intent. Vital status was determined in 1972. Proportional hazards regression estimated mortality rate ratios for men who intentionally lost weight compared with men with no weight change. Analyses were stratified by health status and adjusted for age, initial body mass index, smoking status, alcohol intake, education, physical activity, health history, and physical symptoms. Among men with no reported health conditions (n = 36,280), intentional weight loss was not associated with total, cardiovascular (CVD), or cancer mortality, but diabetes-associated mortality was increased 48% (95% confidence interval (CI) -7% to +133%) among those who lost 20 pounds (9.1 kg) or more; this increase was largely related to non-CVD mortality. Among men with reported health conditions (n = 13,057), intentional weight loss had no association with total or CVD mortality, but cancer mortality increased 25% (95% confidence interval -4% to +63%) among those who lost 20 pounds or more. Diabetes-associated mortality was reduced 32% (95% confidence interval -52% to -5%) among those who lost less than 20 pounds and 36% (95% confidence interval -49% to -20%) among those who lost more than 20 pounds. These results and those from our earlier study in women (Williamson et al., Am J Epidemiol 1995;141:1128-41) suggest that intentional weight loss may reduce the risk of dying from diabetes, but not from CVD. In observational studies, however, it is difficult to separate intentional weight loss from unintentional weight loss due to undiagnosed, underlying disease. Well-designed observational studies, as well as randomized controlled trials, are needed to determine whether intentional weight loss reduces CVD mortality.