Abstract Purpose: Sexual minority (SM) populations (including people who are lesbian, gay, or bisexual) may have higher cancer risk attributable to social determinants of health (SDOH) such as limited healthcare access, discrimination, and a lack of culturally sensitive care. SM people have higher chronic physiological stress, or allostatic load (AL) compared to their heterosexual peers. Furthermore, SM individuals with high AL have more than twice the risk of cancer mortality than heterosexual people with high AL. Here, we examined the mediating effects of SDOH on the relationship of SM identity and AL with cancer mortality risk. Methods: We performed a retrospective analysis of 2001-2010 data from 12,470 participants in the National Health and Nutrition Examination Survey (NHANES) linked to follow-up data from the National Death Index through 12/31/2019. We calculated descriptive statistics across groups defined by SM status and AL (e.g. SM with high AL, SM with low AL, heterosexual with high AL, and heterosexual with low AL) and performed survey-weighted Cox regression to assess the association of sexual orientation/AL with cancer mortality risk. We examined the mediating effects of an individual’s SDOH including household income, self-reported general health condition, whether they attended routine health visits, whether they saw a mental health professional in the past year, location of healthcare visits, poverty to income ratio, self-reported prior health condition, and the number of health visits in the past year. Results: Compared to heterosexual individuals with low AL, SM people with high AL were more likely to report: an annual household income < $20,000 (22.7% vs. 12.8%), living in a single person household (22.5% vs. 8.7%), poor general health condition (7.1% vs. 1.3%), worse health now versus one year ago (16.3% vs. 7.8%), seeing a mental health professional within the past year (21.3% vs. 7.9%), and being in the lowest poverty to income ratio quartile (19.4% vs. 13.9%) (p values < 0.001). Among SM adults with high AL, cancer mortality risk was increased 5-fold (age adjusted HR: 4.89, 95% CI: 2.59 – 9.23) versus heterosexual adults with low AL. Upon additional adjustment for sociodemographic factors (age, race/ethnicity, education status, and gender), the association attenuated but remained significant (adjusted HR: 3.31, 95% CI: 1.77 – 6.16). The following factors all slightly mediated the relationship of SM status and high AL with cancer mortality risk: household income (% mediated = 12.35, p < 0.01), seeing a mental health provider within past year (% mediated = 9.88, p < 0.05), greater number of healthcare visits within past year (% mediated = 8.31, p < 0.05), and poor self-reported general health condition (% mediated = 14.08, p < 0.05). Conclusion: Among a nationally representative sample of more than 12,000 US adults, we observed many SDOH significantly mediate the relationship of SM status and high AL with cancer mortality risk. These results can help inform the identification of intervention points to lessen health disparities. Citation Format: Alisha Patel, Justin X. Moore, Missy Spears, Tracy Casanova, Brent Shelton, Heidi Weiss, Marvin E. Langston, Keith J. Watts, Donte Boyd, Prajakta Adsul, Meredith Duncan. Mediating role of social and health factors on the relationship between sexual minority individuals living with high allostatic load and risk of cancer mortality [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 B157.