Abstract Pancreatic cancer is one of the deadliest malignancies in the US. Most cases are diagnosed in the late, non-resectable stages largely due to lack of effective screening tests. There is an urgent need to identify modifiable risk factors for primary prevention of this malignancy. To date, only a few risk factors (family history, smoking, and type-2 diabetes) have been identified for pancreatic cancer. Although several lines of evidence suggest that nutrition plays a role in pancreatic cancer, few nutrients have been consistently associated with its risk in epidemiologic studies. Therefore, the present study sought to investigate the association between the 2015 Healthy Eating Index (HEI-2015) score and pancreatic cancer risk among participants in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). The HEI-2015 is a measure of overall diet quality used to assess how well a diet conforms to key recommendations of the 2015-2020 Dietary Guidelines for Americans. The HEI score is made up of 13 food components, with higher scores (ranged 0-100 points) indicating better dietary quality. In the present study, the HEI-2015 scores were calculated from participant responses to two food frequency questionnaires, dietary questionnaire (DQX) and dietary history questionnaire (DHQ) administered at baseline and the three-year anniversary of enrollment, respectively. During a median follow-up of 12.2 years, 279 cases of pancreatic cancer were identified among 58,477 participants who completed the DQX, while 101,721 participants who responded to the DHQ gave rise to 380 cases of pancreatic cancer over a median follow-up of 8.9 years. Hazard ratios (HR) and 95% confidence internals (CI) were estimated using Cox proportional hazards regression for total HEI score and individual score components, classified into adequacy components (total fruit, whole fruits, total vegetables, greens and beans, whole grains, dairy, total protein foods, seafood and plant proteins, and fatty acids) and moderation components (refined grains, sodium, added sugars, and saturated fats). After adjustment for confounders, no significant association between total HEI score and pancreatic cancer was identified [HR (95% CI) for quartile (Q) 4 vs. Q1: 0.86 (0.60, 1.09) for DQX and 1.03 (0.77, 1.39) for DHQ]. The individual component scores for total vegetables and added sugar in the DHQ analysis and whole grain score in the DQX analysis were inversely associated with pancreatic cancer risk [HR (95% CI) for one-point score increase: 0.89 (0.81, 0.98), 0.95 (0.91, 0.99), and 0.94 (0.89, 0.99), respectively]. In summary, our study did not find a significant association between overall diet quality and pancreatic cancer risk but revealed significant associations with total vegetables, added sugar, and whole grains in the PLCO trial. Citation Format: Margaret L. Hoyt, Jianjun Zhang. Association between healthy eating index score and risk of pancreatic cancer in the prostate, lung, colorectal, and ovarian cancer screening trial (PLCO) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2586.