PURPOSE Hepatocellular carcinoma (HCC) related to non-alcoholic fatty liver disease (NAFLD, now MASLD) is a growing health concern worldwide particularly in areas of high endemicity such as Latin America. The region has a uniquely mixed population of high ancestral diversity which has been minimally studied. We aimed to assess the role of ancestry in HCC risk factors in Latin America. METHODS We retrospectively evaluated data from the ESCALON network, a European-Latin American network that prospectively follows patients with HCC to assess clinical, demographic, and ancestral parameters. A total of 429 individuals with HCC from 6 countries in Latin America were studied: Argentina (34% N: 145), Chile (15% N: 66), Ecuador (15% N: 63), Peru (15% N: 66), Colombia (14% N: 60), and Brazil (7% N: 29). Self-reported ancestry was categorized as European or Non-European which included the following: Amerindian or Indigenous, African, Asian, or other. HCC was diagnosed per standard AASLD guidelines. RESULTS 131 patients (30.5%) reported having European ancestry and 298 (69.5%) non-European ancestry. Median age in both cohorts was 68 years. 72% of patients in the European cohort were male compared to 62% in the non-European cohort. The most common etiology for HCC in the European cohort was hepatitis C virus (38%) compared to NAFLD (52%) in the non-European cohort. Alcohol use disorder was the second most common etiology in both groups (25% European, 23% Non-European). Both European and Non-European ancestry cohorts had a similar proportion of HCC diagnosed under surveillance (40% and 41%, respectively) and similar presence of extrahepatic disease (47% and 50%, respectively). Interestingly, self-reported ancestry was associated with differential proportions of certain genetic polymorphisms including STAT4 and MBOAT7, suggesting a correlation between self-reporting of ancestry and genetic expression. CONCLUSION NAFLD-HCC was more common in Latin American patients of non-European descent compared to those of European descent, suggesting that ancestry may contribute to underlying liver disease, and in turn, the risk for HCC. However, larger studies including admixture analyses are needed to better understand this interaction.