Introduction: Hepatocellular carcinoma (HCC) represents the second most common cause of cancer-related death worldwide. Over the last decade non-alcoholic fatty liver disease (NAFLD) has emerged as an important cause of HCC. Despite South America having one of the world’s highest prevalence of NAFLD, little is known about NAFLD-related HCC from the region. Methods: Through the South American Liver Research Network (SALRN) we identified 1336 patients with HCC across 14 centers in six countries in South America (2005-2015). We used a retrospective study design with data collected via a templated chart of patient characteristics completed by participating centers. Diagnosis of HCC was made via radiological or histologic findings for all cases according to institutional standards, and each center was responsible for ethical approval. We later performed a focused analysis on HCCs related to NAFLD and compared epidemiological variables to the overall HCC cohort. Results: A total of 111 patients (8.3% of the total HCCs) in our cohort had NAFLD as the underlying disease leading to HCC. Of these, 44% were females compared to 32% in the all-cause cohort. The median age of diagnosis was relatively similar in patients with NAFLD-HCC compared to all-cause HCC (67 vs 64 years), except in Ecuador where NAFLD-HCC had a younger age of diagnosis at 55 years (IQR 52-58). Ecuador also reported a higher percent of females with NAFLD-HCC (83%). When compared to all-cause HCC, a similar number of NAFLD-HCC were diagnosed via surveillance (52% vs 48%), and most had underlying cirrhosis (88%). Fewer patients with NAFLD-HCC received curative treatment (radiofrequency ablation, resection, transplant) when compared to all HCC (31% vs 35%), and those with NAFLD-HCC who underwent surveillance were more likely to have curative treatment (37% vs 15%). Mean survival for NAFLD-HCC patients was lower than mean survival for all HCC patients but the difference was not significant (9.9 vs 11 months P = 0.57). Conclusion: Our findings focused on South America suggest that NAFLD-related HCC affects women more frequently than other causes and the great majority of patients have underlying cirrhosis. Interestingly, there was a trend towards lower survival in those with NAFLD-HCC.