Introduction: Hepatocellular carcinoma (HCC) related to non-alcoholic fatty liver disease (NAFLD) is a growing health concern worldwide and particularly in areas of high NAFLD endemicity such as Latin America. This region has a mixed population with a diverse heritage that is rarely accounted for when looking at epidemiological studies. We assessed the differences in the epidemiology and outcomes of HCC in Latin Americans based on self-reported ancestry. Methods: We retrospectively evaluated data from the ESCALON network, which prospectively follows patients at risk of and with HCC in 6 countries in South America. Self-reported ancestry data was categorized as European, Amerindian, African, Asian, Indigenous, or other. For this study we divided ancestry in 2 categories: European and non-European. Individuals in each category were evaluated using comparative statistics for demographics, underlying liver disease, tumor characteristics and treatment. IRB approval was obtained from all participating institutions. Results: 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). The median age was 68 years and 65% were male. 131 patients (30.5%) reported a European ancestry and 298 (69.5%) non-European ancestry. In those of European ancestry median age was 66 years and 72% were male. In the non-European ancestry cohort median age was 67 years and 62% were male. The most common causes of underlying liver disease were hepatitis C virus (38%) followed by alcohol use disorder (25%) in European ancestry and NAFLD (52%) followed by alcohol use disorder in non-European ancestry (23%). Both groups, European and non-European ancestry, had similar proportion of HCC diagnosed under surveillance (40% and 41% respectively) and similar presence of extrahepatic disease (47% and 50% respectively). 26% of those with European ancestry received curative therapy compared to 33% of those with non-European ancestry. Conclusion: This is the first study addressing ancestry in Latin Americans with HCC. We found that HCC related to NAFLD was more common in patients of non-European descent. Future studies are warranted to better understand the impact of genetics within specific regions of the continent to understand risk of HCC.