Epidemiological studies are remarkably consistent, especially among men, in showing that overweight and obesity [body mass index (BMI) >25] are associated with increased risk of colon cancer. However, no prospective studies address the influence of weight change in adulthood on subsequent colon cancer risk. In this study, we investigated whether weight change influences colon cancer risk utilizing prospectively collected weight data. We included 46,349 men aged 40–75 participating in the Health Professionals Follow-Up Study. Questionnaires including items on weight were completed every second year during follow-up from 1986 to 2004. Updated weight change between consecutive questionnaires during follow-up and recalled weight gain since age 21 was evaluated. All eligible men were cancer-free at baseline. Proportional hazard and restricted spline regression models were implemented. Over an 18-year period, we documented 765 cases of colon cancer. Cumulative mean BMI >22.5 was associated with significantly increased risk of colon cancer. The short-term weight change in the prior 2 to 4 years was positively and significantly associated with risk [HR = 1.14 (95% confidence interval, 1.00–1.29) for 4.54 kg (10 pounds) increment, p = 0.04 for overall trend]. Weight gain per 10 years since age 21 was associated with significantly increased risk [HR = 1.33 (1.12–1.58) for 4.54 kg increase per 10 years, p = 0.001]. We estimated that 29.5% of all colon cancer cases was attributable to BMI above 22.5. Our results add support that overweight and obesity are modifiable risk factors for colon cancer among men and suggest that weight has an important influence on colon cancer risk even in later life. © 2008 Wiley-Liss, Inc.