Introduction: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Most studies have focused on characterizing patients with HCC in Europe, North America, and Asia. However, little is known about the underlying demographic characteristics and risk factors for HCC in South America. Methods: This study is a retrospective cohort study aimed at identifying the risk factors and demographics of HCC in South America. Participating centers completed a templated, retrospective chart review of patient characteristics at the time of HCC diagnosis. Results: Fourteen centers from six countries contributed data for an aggregate 1,336 patients. Brazil accounted for 40% of patients, Argentina 19%, Colombia 18%, Peru 16%, Ecuador 5% and Uruguay 2%. The median age at diagnosis was 64 years and 68% were male. The most common risk factor for HCC was HCV (48%), followed by alcoholic cirrhosis (22%), HBV (14%), NAFLD (9%) or other (8%). Other subgroups included 727 patients with treatment data and 241 patients with survival data. Logistic regression models showed absence of cirrhosis (OR 3.96, 95% CI 2.09-7.44, p= < 0.001), diagnosis with HCC surveillance (OR 2.21, 95% CI 1.43-3.47, p= < 0.001) and AFP < 200ng/ml at the time of diagnosis (OR 2.29, 95% CI 1.25-4.24, p=0.007) were predictive of receiving curative therapy. NAFLD, gender, AFP < 20ng/ml, age, HBV, HCV and alcoholic liver disease were not significant. A COX proportional hazards model showed significant improvements in survival were associated with screening (RR 1.62, 95% CI 1.28-2.07, P= < 0.001), age (RR 1.01, 95% CI 1.00-1.02, p=0.025) and HCV (RR 1.35, 95% CI 1.01-1.80, p=0.042). Covariates, including HBV, alcoholic liver disease, NAFLD, cirrhosis, AFP level and curative therapy were not significant. Conclusion: Our study is the largest cohort to date reporting demographics, risk factors, and outcomes of HCC patients across South America. We found that patients without cirrhosis, patients with an AFP < 200ng/ml or patients who were diagnosed on screening were more likely to receive curative therapy as defined by surgical resection, radiofrequency ablation, alcohol ablation or liver transplant. We also showed that age, screening protocol use and underlying HCV were independently associated with prolonged survival.