We aim to describe the efficacy, safety profile, and variables associated with survival in patients with hepatocellular carcinoma (HCC) treated with sorafenib in South America.Sorafenib has been shown to improve survival in patients with advanced HCC. There are few data on sorafenib use for HCC in South America.We performed a retrospective analysis of HCC cases treated with sorafenib from 8 medical centers in 5 South American countries, between January 2010 and June 2017. The primary endpoint was overall survival (OS), which was defined as time from sorafenib initiation to death or last follow-up. Risk factors for decreased OS were assessed using Cox proportional hazard regression and log-rank tests.Of 1336 evaluated patients, 127 were treated with sorafenib and were included in the study. The median age of individuals was 65 years (interquartile range, 55 to 71) and 70% were male individuals. Median OS in all patients was 8 months (interquartile range, 2 to 17). Variables associated with survival on multivariate analysis were platelets >/<250,000 mm (2 vs. 8 mo, P=0.01) and Barcelona Clinic Liver Cancer (BCLC) stage (A/B, 13 vs. C/D, 6 mo; P=0.04). In a subanalysis of patients with BCLC stage C, platelets >/<250,000 mm were also independently associated with survival (2 vs. 5.5 mo, P=0.03). Patients lived longer if they experienced any side effects from sorafenib use (11 vs. 2 mo, P=0.009). Patients who stopped sorafenib because of side effects had shorter survival compared with patients who were able to tolerate side effects and continue treatment (7.5 vs. 13 mo, P=0.01).Pretreatment elevation of platelets and advanced BCLC stage were independently associated with poor survival on sorafenib in a South American cohort.