BACKGROUND: The transforming growth factor-beta-signaling pathway has been identified as being involved in colorectal cancer. OBJECTIVE: The aim of this study was to determine how diet and lifestyle factors in combination with genetic variation in the transforming growth factor-beta-signaling pathway alters colorectal cancer risk. DESIGN: We used data from 2 population-based case-control studies. PATIENTS: Participants included patients with colon cancer (n = 1574) and controls (n = 1970) and patients with rectal cancer ( n = 791) and controls (n = 999). MAIN OUTCOME MEASURES: The primary outcomes measured were newly diagnosed cases of colon or rectal cancer. RESULTS: Colon and rectal cancer risk increased with the number of at-risk genotypes within the transforming growth factor-beta-signaling pathway (OR 3.68, 95% CI 2.74,4.94 for colon cancer; OR 3.89, 95% CI 2.66,5.69 for rectal cancer). A high at-risk lifestyle score also resulted in significant increased risk with number of at-risk lifestyle factors (OR 2.99, 95% CI 2.32,3.85 for colon cancer; OR 3.37, 95% CI 2.24,5.07 for rectal cancer). The combination of high-risk genotype and high-risk lifestyle results in the greatest increase in risk (OR 7.89, 95% CI 4.45,13.96 for colon cancer; OR 8.75, 95% CI 3.66,20.89 for rectal cancer). LIMITATIONS: The study results need validation in other large studies of colon and rectal cancer. CONCLUSIONS: In summary, our data suggest that there is increased colon and rectal cancer risk with increasing number of at-risk genotypes and at-risk lifestyle factors. Although the integrity of the pathway can be diminished by a number of high-risk genotypes, this risk can be offset, in part, by maintaining a healthy lifestyle.