Abstract Background: Pancreatic cancer is one of the deadliest cancers, and its incidence has been increasing steadily in the past decade. While some dietary components have been implicated as risk factors for pancreatic cancer, epidemiological data on the role of overall diet quality in pancreatic cancer etiology are limited, especially from population-based prospective studies. This study examined the relationship between diet quality and pancreatic cancer incidence in the Multiethnic Cohort Study (MEC). Methods: Data were analyzed from 177,313 African American, Native Hawaiian, Japanese American, Latino, and White men and women aged 45-75 years who completed a quantitative food frequency questionnaire at cohort entry. Diet quality was assessed by a priori diet quality indices (DQIs), the Healthy Eating Index-2015 (HEI-2015), the Alternative Healthy Eating Index-2010 (AHEI-2010), the alternate Mediterranean Diet (aMED) score, the Dietary Approaches to Stop Hypertension (DASH) score, and the Dietary Inflammatory Index (DII®). These five DQIs were investigated because of their potential to capture differences in various nutritional patterns across different racial/ethnic groups. Multivariate Cox models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the DQIs and pancreatic cancer incidence adjusted for age, sex, race/ethnicity, education, diabetes status, family history of pancreatic cancer, vigorous physical activity, smoking status with pack years, total energy intake, body mass index (BMI), and alcohol consumption. Stratified analyses were done by sex, race/ethnicity, smoking status and BMI. Results: During an average follow up of 19.3 years, 1,782 incident pancreatic cancer cases were identified. Overall, we did not observe statistically significant associations between the DQIs and pancreatic cancer risk. In subgroup analyses comparing the highest vs. lowest quintiles of the scores, a protective association was observed with the DASH for ever smokers (HR = 0.75, 95% CI: 0.60-0.92) and individuals with BMI ≥ 25 kg/m2 (HR = 0.77, 95% CI: 0.63-0.94), but not for never smokers (HR = 1.04, 95% CI: 0.82-1.31, P for heterogeneity = 0.004) or those with BMI < 25 kg/m2 (HR = 1.21, 95% CI: 0.94-1.56, P for heterogeneity = 0.097). There were no differences in associations by sex or race/ethnicity (P for heterogeneity ≥ 0.43). Conclusion: In this large prospective study, we did not find reduction in pancreatic cancer risk associated with healthier diet as assessed by the 5 DQIs. There is some indication that adherence to the DASH diet may potentially be protective against pancreatic cancer among ever smokers or individuals classified as overweight or obese. Further investigations are needed to confirm these findings. Citation Format: Heather Steel, Song-Yi Park, Tiffany Lim, Daniel Stram, Loic Le Marchand, Anna H. Wu, V. Wendy Setiawan. Diet quality and pancreatic cancer incidence in the Multiethnic Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5870.