The authors investigated the relations of body mass index at different ages and adult weight change to incident colorectal cancer risk in the prospective National Institutes of Health-AARP Diet and Health Study (1995-1996), using a subcohort with repeated recall weights (273,679 participants; mean baseline age = 62.8 years). During 2,509,662 person-years follow-up, 4076 incident colorectal cancers were ascertained. For men, an increased risk of colon cancer but not rectal cancer was associated with body mass index at baseline age (per 5-kg/m(2) increase, hazard ratio (HR) = 1.18, 95% confidence interval (CI): 1.11, 1.25), at age 50 years (HR = 1.18, 95% CI: 1.10, 1.26), and at age 35 years (HR = 1.16, 95% CI: 1.07, 1.25) but less so at age 18 years. Weight gained between the ages of 18 and 35 years and between 18 years of age and the baseline age was associated with an increased risk of colon cancer in men (per 0.5-kg/year increase, HR = 1.18, 95% CI: 1.11, 1.25 and HR = 1.29, 95% CI: 1.16, 1.56, respectively). For women, relations throughout were weaker than those observed for men. These findings suggest that weight gains during early to middle adulthood have important influences on colon cancer risk, especially in men.