Abstract Introduction: Non-Hispanic Black colorectal cancer (CRC) patients have a higher risk of mortality compared to most other racial/ethnic groups. Limited studies examine the contribution of socioeconomic (SES), clinicopathologic, or treatment variations toward mortality disparities. This retrospective cohort investigation examined the extent to which SES, clinicopathologic, and treatment factors explain racial/ethnic differences in CRC mortality. Methods: We studied 146,515 individuals ,18+ years old, with a confirmed diagnosis of CRC within 2010-2017 identified from the Surveillance, Epidemiology, and End Results (SEER) database. We performed Cox regression analyses to examine the association of race/ethnicity, surgery type, and tumor site with all-cause mortality and CRC-specific mortality. We then performed mediation analysis to quantify the extent to which mortality differences were mediated by SES, clinicopathologic, and treatment factors. Results: Non-Hispanic Black patients had a significantly higher hazard of all-cause mortality than non-Hispanic White patients. The non- Hispanic White versus non-Hispanic Black patients’ comparison demonstrated that variations in SES and clinicopathologic factors significantly explained 46.63% (indirect effect HR: 0.92, 95% CI 0.91-0.93) and 10.87% (indirect effect HR: 0.98, 95% CI 0.97-99) of the excess all-cause mortality among non-Hispanic Black patients, respectively. The Hispanic vs. non-Hispanic Black comparisons identified SES as the most influential mediator, explaining 19.68% of the excess all-cause mortality. The proportions mediating for CRC-specific mortality showed comparable outcomes to all-cause mortality. Conclusions Non-Hispanic Black patients had greater risk for all-cause mortality and CRC-specific mortality attributed to SES and clinicopathologic variations compared to other racial/ethnic groups. Future studies should investigate equity in healthcare through interventions addressing SES-related disparities. Citation Format: Pierre Fwelo, Toluwani E. Adekunle, Tiwaladeoluwa B. Adekunle, Ella R. Garza, Emily S. Huang, Wayne R. Lawrence, Aldenise P. Ewing. Differential colorectal cancer mortality across racial and ethnic groups: Impact of socioeconomic status, clinicopathology, and treatment-related factors [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C155.