Abstract Background: Colorectal cancer (CRC) accounts for a greater proportion of all cancer deaths among Hispanic/Latino/a/x (H/L) individuals compared to Non-Hispanic White (NHW) subjects. However, the tumor landscape and key determinants of outcomes for CRC among H/L patients remain understudied. Methods: As a Cancer Moonshot initiative, we launched the “Enfrentando el Cancer en Comunidad” (ENLACE) study, which engages H/L CRC patients to characterize their germline genetics and tumor genomic landscape, and to collect data to identify determinants of participation in genetics/genomics research and cancer outcomes. H/L CRC patients >=18 years of age are being recruited from two healthcare facilities: a safety-net hospital, Los Angeles General Medical Center (LA Gen), and a university medical center, USC Norris Comprehensive Cancer Center (Norris). An H/L bilingual team administered surveys to assess patient demographics, acculturation level, Latino values, health literacy, numeracy, CRC risk factors, genetics knowledge (Knowgene scale), and generalized self-efficacy (GSE) upon recruitment for the study, and after return-of-results (ROR) of somatic and germline testing. Results: 165 H/L CRC patients have joined the ENLACE study, with 105 completing baseline surveys (56 male, median age 53 (IQR = 45-60)), and 39 with finalized ROR. Most of the participants self-identified as White (58.1%), were Mexico-born (52.4%), and married (50%). Patients from Norris (n = 33) were more likely to be US-born (55%), college graduates (21%), and annually earn at least $100,000 (69%) while employed full-time (45%) than LA Gen patients (all p-values <0.01). Additionally, Norris patients had higher numeracy and health literacy scores at baseline than LA Gen (p = 0.006 & p = 0.042, respectively). LA Gen patients (n = 72) showed higher scores for familism, respect, traditional gender roles, material success, and mainstream values in the Latino-American cultural values scale (all p-values < 0.05). Higher levels of GSE across all patients were associated with increased numeracy (p = 0.014). LA Gen participants with a higher score for GSE, had on average, higher subscores for material success (p = 0.011), competition and personal achievements (p = 0.07), and mainstream values (p = 0.051), and decreased uncertainties about genetic testing (p = 0.05). A multivariable logistic regression model adjusted for treatment facility, acculturation, age, gender, and income reported that a 1 unit increase in numeracy was statistically significantly associated with 1.62 times the odds of having a greater than the median GSE score (95% CI: 1.09-2.39, p = 0.016). After ROR, a decrease in the number of times participant selected “Don’t know” in the KnowGene scale was reported (p <0.001). Conclusion: We report differences in baseline characteristics for ENLACE participants across healthcare facilities and determinants of generalized self-efficacy. These findings can help inform future interventions to improve self-efficacy and optimize engagement of H/L patients navigating CRC treatment. Citation Format: Joel Sanchez Mendez, Carmen Chavez, Lucia Enriquez, Julie O Culver, Charité N Ricker, Natalia Gutierrez, Sandra Algaze, Lourdes Baezconde-Garbanati, John D. Carpten, Heinz-Josef Lenz, Mariana C. Stern. Determinants of increased generalized self-efficacy among Hispanic/Latino colorectal cancer patients participating in a Cancer Moonshot 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 A009.