Abstract Background: Cancer is the leading cause of death among Hispanic/Latino adults in the United States (US). However, few studies have examined how cancer incidence varies by Hispanic/Latino heritage. Herein, we describe the incidence rates of cancer overall, for screen- detectable cancers, and for subsets of cancers that share common etiologic factors, including tobacco-related and obesity-related cancers among participants in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Methods: We included 16,415 adults ages 18-74 from the HCHS/SOL, an ongoing population-based prospective cohort study of Hispanic/Latino adults from diverse backgrounds from four field centers (Bronx, NY; Miami, FL; San Diego, CA; and Chicago, IL). The HCHS/SOL cohort participant records were linked to the state cancer registries in New York, Florida, California, and Illinois to ascertain cancer incidence from the baseline examination (2008-2011) through the end of 2021. We used Poisson regression to estimate weighted age-adjusted cancer incidence rates (IRs), and Cox regression to estimate weighted age- and sex-adjusted hazard ratios (HRs) of overall cancer and cancer groups, for all participants combined and by heritage groups. Results: Over a mean follow-up of 10.7 years (5th percentile=7.4, 95th percentile=13.1 years), 715 incident invasive cancers were diagnosed in the HCHS/SOL cohort, including the leading cancers: 118 female breast, 102 prostate, and 79 bronchus and lung cancers. The age-adjusted IR of all cancers combined was 33.7 [95% confidence interval (CI)=29.7-38.1] per 10,000 (10K) person-years (py). IRs of all cancers combined were lowest among persons of Mexican descent [IR=19.0 (95%CI=15.0-24.1) per 10K py] followed by those of Central American [IR=19.7 (95%CI=14.2-27.4) per 10K py], South American [IR=23.0 (95%CI=15.5-34.1) per 10K py], Dominican [IR=26.9 (95%CI=19.8-36.5) per 10K py], Cuban [IR=27.9 (95%CI=21.3-36.4) per 10K py], and Puerto Rican [IR=36.6 (95%CI=28.4-47.0) per 10K py] descent. Compared to those of Mexican descent, those of Puerto Rican descent had a 92% [HR=1.92 (95%CI=1.36-2.72)] higher hazard of cancer, while those of Cuban descent had a 47% [HR=1.47 (95%CI=1.07-2.03)] higher hazard and those of Dominican descent had a 40% [HR=1.40 (95%CI=0.97-2.03)] higher hazard. Compared to other Hispanic/Latino heritage groups, the incidence of obesity-related cancers was the highest among Puerto Ricans, while the incidence of tobacco-related cancers was highest among those of Puerto Rican and Cuban descent. Conclusions: Cancer incidence rates varied by Hispanic/Latino heritage and were masked when Hispanics/Latinos were aggregated into a single group. Understanding disparities in cancer risk by Hispanic/Latino heritage may help tailor cancer prevention and control strategies. Citation Format: Humberto Parada, Ilir Agalliu, Daniela Sotres-Alvarez, Andrew F. Olshan, Kelly R. Evenson, Thomas E. Rohan, Robert C. Kaplan, Caroline A. Thompson, Linda C. Gallo, Frank J. Penedo, Jianwen Cai, Sylvia Wassertheil-Smoller, Bharat Thyagarajan, Stefani N. Thomas, Olga L. Garcia-Bedoya, Gregory A. Talavera. Cancer Incidence in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) – The Onco-SOL Ancillary Study [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 PR015.