OBJECTIVE: We examined the relationship between changes in reported vigorous exercise and self-reported physician-diagnosed diabetes in 25,988 active men. RESEARCH DESIGN AND METHODS: The dose-response relationship between changes in reported vigorous exercise (running distance, change in kilometers per week) and self-reported physician-diagnosed diabetes was followed prospectively for 7.8 +/- 1.8 years (means +/- SD). RESULTS: Logistic regression analyses showed that the log odds for diabetes declined significantly in relation to men's change in running distance (coefficient +/- SE: -0.012 +/- 0.004, P < 0.01), which remained significant when adjusted for BMI (-0.018 +/- 0.003, P < 0.0001). The decline in the log odds for diabetes was related to the distance run at the end of follow-up when adjusted for baseline distance, with (-0.024 +/- 0.005, P < 0.0001) or without (-0.027 +/- 0.005, P < 0.0001) adjustment for BMI. Baseline distance was unrelated to diabetes incidence when adjusted for the distance at the end of follow-up. Compared with men who ran < 8 km/week at the end of follow-up, incidence rates in those who ran > or = 8 km/week were 95% lower between 35 and 44 years of age (P < 0.0001), 92% lower between 45 and 54 (P < 0.0001), 87% lower between 55 and 64 (P < 0.0001), and 46% lower between 65 and 75 (P = 0.30). For the subset of 6,208 men who maintained the same running distance during follow-up (+/-5 km/week), the log odds for diabetes declined with weekly distance run (-0.024 +/- 0.010, P = 0.02) but not when adjusted for BMI (-0.005 +/- 0.010, P = 0.65). CONCLUSIONS: Vigorous exercise significantly reduces diabetes incidence, due in part to the prevention of age-related weight gain and in part to other exercise effects.