Abstract A higher risk of colorectal cancer (CRC) has been associated with high animal fat intake, but not vegetable fat. To date, limited data provides the quantification of the effect exerted by fatty acids (FAs) on CRC overall and by anatomical sub-sites. This study aims to look at associations between some FAs intakes [cholesterol, total fat, total saturated fatty acids (SFAs), total monounsaturated fatty acids (MUFAs), total polyunsaturated fatty acids (PUFAs), total trans fatty acids (TFAs), oleic acid, myristic acid, total ruminant (rTFAs) and industrial fatty acids (iTFAs), eliadic acid (EA), conjugated linoleic acid (CLA), and CRC risk in a large case-control study (IROPICAN) in Iran . We analyzed 865 CRC cases (434 in colon, 404 in rectum, and 27 with unknown subsite) and 3,206 controls from seven provinces of Iran. Detailed information was collected by trained interviewers using validated lifestyle and food frequency questionnaires (FFQ). The different types of total and individual FAs intake were categorized into quartiles of intake. The odds ratios (OR) and 95% confidence intervals (CI) for the association between CRC them were calculated using multivariate logistic regression models by adjusting for the potential confounders. Furthermore, analyses were stratified by age (under and over 50) and also, we repeated the analyses for CRC subsites. There was a statistically significant positive association between CRC and high intake (quartile 4) compared to the low intake (quartile) of dietary total fat (OR=1.77, 95% CI=1.32-2.38), cholesterol (OR=1.58, 95% CI=1.22-2.05), total TFAs (OR=1.31, 95% CI=1.02-1.68), TFAs (OR=1.73, 95% CI=1.12-2.68), EA(OR=2.69, 95% CI=1.46-4.93), and SM (OR=1.45, 95% CI=1.00-2.09), as well as an inverse association with high intake of dietary rTFAs (OR=0.60, 95% CI=0.39-0.93), CLAs (OR=0.34, 95% CI=0.19- 0.60). Stratified analyses by age indicated that there was a statistically significant association between CRC and total fat intake [OR =1.30, 95% CI =1.16-1.46, p=0.006 for the interaction], cholesterol intake [OR =1.22, 95% CI=1.11-1.35, p=0.019 for the interaction], and iTFA intake [OR =1.31, 95% CI=1.06-1.62, p=0.02 for the interaction] after 50 years old. The results of our study indicate that decreasing fat consumption, particularly from industrial and animal sources, may reduce the risk of CRC. Citation Format: Monireh Sadat Seyyedsalehi, Paolo Boffetta, Kazem Zendehdel. Fatty acid intake as potential risk factor of colorectal cancer: A multicenter case control study in Iran [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 6450.