The aim of the study was to evaluate our institutional experience with monotherapies for hepatocellular carcinoma (HCC) in the setting of cirrhosis. A retrospective cohort study was carried out at the tertiary care academic referral center and involved 185 consecutive HCC patients with cirrhosis and no previous treatment who underwent resection (n = 61), transarterial chemoembolization (TACE) (n = 64), or liver transplantation (LT) (n = 60). Long-term survival and survival according to the Milan criteria were the main outcomes measured. Median survival after resection, TACE, and LT was 11, 14, and 23 months, respectively. Five-year cumulative survival after resection, TACE, and LT was 23, 10, and 59%, respectively (P = 0.001). Five-year cumulative disease-free survival after resection and LT was 15% and 77%, respectively (P = 0.002). The presence of complications in the resection group (P = 0.004), MELD score (P = 0.0003), and maximum tumor diameter (P = 0.05) in the TACE group, and tumor grade (P = 0.01) and complications (P = 0.004) in the LT group were found to be independent predictors of survival. Five-year survival for patients within the Milan criteria after resection, TACE, and LT was 26, 37, and 66%, respectively. Five-year survival for patients outside the Milan criteria for patients undergoing LT was 53%. The results suggest that LT represents the best oncological treatment option for patients with HCC in the setting of cirrhosis, even for those beyond the Milan criteria. Considering the scarcity of available organs, liver resection remains the best alternative option. TACE remains a potential therapy in patients within the Milan criteria, where it may be more beneficial than resection.