Whether adiposity is a risk factor for the development of hereditary colorectal cancer (CRC) in patients with Lynch syndrome is unclear. In a prospective study, 937 patients were randomly assigned to receive daily aspirin (600 mg) or placebo. The CRC risk was greater in obese patients than normal-weight or underweight participants. Moreover, obesity was associated with a substantially increased risk of CRC in patients with Lynch syndrome; however, this risk was abrogated in patients taking aspirin. Thus, aspirin could provide benefit as a prevention strategy in these patients.