The relative importance of overweight after childhood and excess weight gain during adulthood remains unclear. In 39,909 male participants of the Health Professionals Follow-Up Study who were 40–75 years of age in 1986 and were followed until 2008, we documented 8,755 incident cases of obesity-related chronic diseases (type 2 diabetes mellitus, cardiovascular diseases, and colorectal, renal, pancreatic, and esophageal cancers). We calculated composite and cause-specific hazard ratios using a model that included body mass index (BMI; weight (kg)/height (m)2) at 21 years of age, weight change since age 21 years, smoking, alcohol consumption, and family histories of myocardial infarction, colon cancer, and diabetes. Compared with a BMI at 21 years of 18.5–22.9, the composite hazard ratio for a BMI of 23–24.9 was 1.22 (95% confidence interval (CI): 1.16, 1.29), that for a BMI of 25.0–27.4 was 1.57 (95% CI: 1.48, 1.67), that for a BMI of 27.5–29.9 was 2.40 (95% CI: 2.17, 2.65), and that for a BMI ≥30.0 was 3.15 (95% CI: 2.76, 3.60). The composite hazard ratios for adult weight gain compared with a stable weight were 1.12 (95% CI: 1.03, 1.22) for a gain of 2.5–4.9 kg, 1.41 (95% CI: 1.31, 1.52) for a gain of 5–9.9 kg, 1.72 (95% CI: 1.59, 1.86) for a gain of 10–14.9 kg, and 2.45 (95% CI: 2.27, 2.63) for a gain ≥15 kg. Adiposity in early adulthood and adult weight gain were both associated with marked increases in the risk of major chronic diseases in middle-aged and older men, and these associations were already apparent at modest levels of overweight and weight gain.