Abstract Background: Carotenoids have been hypothesized to reduce the development of colorectal adenomas through their antioxidant and provitamin A properties. However, only a few studies have examined these associations. Method: In the Health Professionals Follow-up Study, a prospective cohort study, 4,448 cases of colorectal adenoma were identified among the 29,248 men who reported receiving a lower bowel endoscopy between 1986 and 2006. Participants completed food frequency questionnaires every 4 years; dietary information was cumulatively updated. When examining the overall effect of total carotenoid intake, we used a total carotenoid score created by summing the quintile levels for each individual carotenoid to take into account different intake levels across specific carotenoids. The associations between α-carotene, β-carotene, β-cryptoxanthin, lycopene, and lutein/zeaxanthin intakes and risk of colorectal adenomas overall and by location and stage were investigated using multivariate logistic regression models. Results: β-carotene, lycopene and lutein/zeaxanthin intakes and the total carotenoid score were inversely associated with risk of colorectal adenomas. The multivariate odds ratios (95% CI) comparing the highest quintile of intake with the lowest were 0.81 (0.72-0.91) for β-carotene, 0.78 (0.70-0.87) for lycopene, 0.84 (0.76-0.94) for lutein/zeaxanthin, and 0.85 (0.76-0.95) for the total carotenoid score. Associations for α-carotene and β-cryptoxanthin intakes were null. For intakes of β-carotene, lycopene, lutein/zeaxanthin and the total carotenoid score, for comparisons of the highest versus lowest quintile of intake, significant 22-32% lower risks were observed for adenomas of the distal colon and rectum but weaker, nonsignificant associations were observed for adenomas of the proximal colon. However, the differences by adenoma site were nonsignificant for each carotenoid (all p-values, test for common effects ≥ 0.14). The association for each carotenoid did not vary significantly by smoking status or alcohol consumption (all p-values, test for interaction≥ 0.15). However, among nondrinkers, the multivariate odds ratio (95%CI) comparing the highest vs lowest quintile were 0.64 (0.46-0.89) for -carotene and 0.70 (0.51-0.95) for lutein/zeaxanthin whereas inverse associations were not observed among alcohol drinkers. When smoking status and alcohol consumption was considered simultaneously, a synergistic interaction between smoking status, alcohol consumption, and carotenoid intake and colorectal adenoma risk was not observed for each carotenoid (all p-values, test for interaction≥ 0.24). For example, for -carotene, the most commonly examined carotenoid, the multivariate odds ratios (95% CI) comparing the highest versus lowest quintile were 0.64 (0.41-1.01) for non-smokers/nondrinkers and 0.86 (0.66-1.12) for current smokers/men drinking at least 15 grams of alcohol/day (p-value, test for interaction = 0.57). The association for each carotenoid did not vary by stage (all p-values, test for common effects ≥ 0.15). Conclusion: This study provides modest evidence that foods high in carotenoids may reduce the risk of colorectal adenomas, particularly of the distal colon and rectum. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A81.