OBJECTIVE: To estimate the effect of intentional weight loss on mortality in overweight individuals with diabetes. RESEARCH DESIGN AND METHODS: We performed a prospective analysis with a 12-year mortality follow-up (1959-1972) of 4,970 overweight individuals with diabetes, 40-64 years of age, who were enrolled in the American Cancer Society's Cancer Prevention Study I. Rate ratios (RRs) were calculated, comparing overall death rates, and death from cardiovascular disease (CVD) or diabetes in individuals with and without reported intentional weight loss. RESULTS: Intentional weight loss was reported by 34% of the cohort. After adjustment for initial BMI, sociodemographic factors, health status, and physical activity, intentional weight loss was associated with a 25% reduction in total mortality (RR = 0.75; 95% CI 0.67-0.84), and a 28% reduction in CVD and diabetes mortality (RR = 0.72; 0.63-0.82). Intentional weight loss of 20-29 lb was associated with the largest reductions in mortality (approximately 33%). Weight loss >70 lb was associated with small increases in mortality CONCLUSIONS: Intentional weight loss was associated with substantial reductions in mortality in this observational study of overweight individuals with diabetes.