Abstract Background. Colorectal cancer (CRC) is a commonly diagnosed cancer. Glucose intake enhances the secretion of insulin, may contribute to cell growth and proliferation, leading to CRC development. Epidemiologic studies have shown that individuals with diabetes history are at increased risk of CRC. A low-carbohydrate diet, represented by a low-carbohydrate diet (LCD) score, may reduce the risk of diabetes. Yet, little is known about the association between LCD scores and the risk of CRC. Methods. We evaluated the associations between LCD and CRC risk in the Singapore Chinese Health Study, a population-based prospective cohort study that includes 61,321 Chinese men and women in Singapore who were 45-74 years old at enrollment. Food and dietary supplement consumption were assessed by a validated semi-quantitative food frequency questionnaire. Participants were assigned a score from 0 to 10 according to their rankings by daily intake of calories from carbohydrates, fat and protein, respectively. A score of 0 was assigned to a subject ranked in the highest one-eleventh of calorie intake from carbohydrates or in the lowest one-eleventh of calories from fat or protein, respectively. In contrast, a score of 10 was given to each subject in the lowest one-eleventh of carbohydrate intake or the highest one-eleventh of fat or protein intake. The LCD score for each subject was the sum of the 3 individual ranking scores. The highest possible value was 30, which represented the lowest carbohydrate intake and the highest fat and protein. In addition, animal-based and plant-based LCDs were similarly created from the daily consumption of calories from animal or plant protein and fat, respectively, as well as carbohydrates. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs) for CRC according to higher quartiles of LCD scores with adjustment for potential confounders. Results. After an average of 17.5 years of follow-up, 2,140 participants developed CRC. Overall, there was a null association between total LCD and CRC risk. A moderate positive association was found for animal-based LCD with CRC risk. The multivariable-adjusted HRs(95%CIs) for CRC in quartiles 2, 3, and 4 of animal-based LCD were 1.12(0.99-1.26), 1.18(1.04-1.33), and 1.11(0.98-1.25)(Ptrend=0.06) compared with the lowest quartile. There were no statistically significant differences in the animal-based LCD and CRC risk in subgroups stratified by sex, body mass index, smoking status, and history of type 2 diabetes. Conclusions. This large population-based prospective cohort study shows that a high animal-based LCD score, which represented low intake of carbohydrates and high intake of animal protein and fat, was associated with ~10% increased risk of CRC. Our findings suggest that replacing low-carbohydrate food with animal-based food may increase the risk of developing CRC. Citation Format: Yi-Chuan Yu, Pedram Paragomi, Aizhen Jin, Renwei Wang, Robert E. Schoen, Woon-Puay Koh, Jian-Min Yuan, Hung N. Luu. Low-carbohydrate diet score and the risk of colorectal cancer: Findings from a prospective cohort study [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 735.