Abstract Pancreatic cancer is the third leading cause of cancer-related death in the U.S. and has a 5-year relative survival rate of only 11.5%. The etiology of pancreatic cancer is not well understood, with cigarette smoking, type 2 diabetes, and chronic pancreatitis as the only well-established risk factors. Therefore, it is critical to identify modifiable risk factors for primary prevention. Persistent oxidative stress and resultant oxidative damage can lead to accumulated mutations in oncogenes and tumor suppressor genes and subsequent carcinogenesis of the pancreas. Carotenoids are abundant in fruits and vegetables, while tocopherols are rich in oilseeds and nuts. Both carotenoids and tocopherols have antioxidant functions. Thus, it is possible that high intake of these bioactive compounds can reduce risk of pancreatic cancer. The present study sought to investigate this question in a case-control study conducted during 1994-1998 in Minnesota. Cases (n=150), aged 20 years or older, were ascertained from all hospitals in the metropolitan area of the Twin Cities and the Mayo Clinic; from the latter, only cases residing in the Upper Midwest of the US were recruited. Controls (n=459) were randomly selected from the general population and frequency matched to cases by age (within 5 years) and sex. Intake of carotenoids and tocopherols from diet and supplements was estimated from a validated food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression. As lutein and zeaxanthin are isomers that have identical chemical formulas, they are combined into a single variable in the analysis. All dietary variables were adjusted for energy intake with the residual method prior to data analysis. After adjustment for age, sex, race, education, physical activity, cigarette smoking, and alcohol consumption, intake of lutein and zeaxanthin was associated with a significantly reduced risk of pancreatic cancer [OR (95% CI) for quartile 4 (median: 4972 µg/day) vs. quartile 1 (median: 976 µg/day): 0.39 (0.19-0.79); p-trend: 0.06]. This inverse association became slightly weaker but remained statistically significant after additional adjustment for intake of energy, fat, and fiber. No significant associations were observed for intake of α-carotene, β-carotene, lycopene, β-cryptoxanthin, α-tocopherol, β-tocopherol, and δ-tocopherol, although a higher intake of all these nutrients except α-tocopherol and δ-tocopherol tended to confer a lower risk. Our study shows that there is a significant, beneficial effect of lutein and zeaxanthin intake on pancreatic cancer risk, although it may be a chance finding due to multiple comparisons. More epidemiologic studies are warranted to further elucidate the roles of carotenoids and tocopherols in the etiology and prevention of pancreatic cancer. Citation Format: Bronson Dokmanovich, Hao fan, Yunpeng Yu, Kristin Anderson, Jianjun Zhang. Carotenoid and tocopherol intake in relation to pancreatic cancer risk in a population-based case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6447.