Background The prognosis of unresectable large hepatocellular carcinomas is poor.This study evaluated the efficacy and safety of sorafenib combined with transcatheter arterial chemoembolization and radiofrequency ablation in the treatment of hepatocellular carcinomas larger than 5 cm.Methods The treatment of 22 patients with large,unresectable hepatocellular carcinomas (5.0-16.5 cm) treated with sorafenib after transcatheter arterial chemoembolization combined with radiofrequency ablation between 2007 and 2011was reviewed.The local effects,survival rates,toxicity,and prognostic factors were analyzed.Results During a follow-up of 9-49 months,19 patients died and three survived.The median overall survival was 32 months.The overall cumulative 12,24,and 36-month survival rates were 85.9％,66.8％,and 23.5％ respectively.Technical effectiveness was achieved in 12 out of 28 lesions (42.85％) at the first CT check.The median time to tumor progression was 21 months.The progression-free survival rates at 6,12,and 24 months were 90.9％,72.0％,and 38.4％,respectively.Combined therapy was generally well tolerated.There was only one major procedure-related complication,biloma (4.5％).Sorafenib-related adverse events exceeding grade 3 were hand-foot skin reaction (2/22,9.1％),gastrointestinal hemorrhage (1/22,4.5％),and diarrhea (2/22,9.1％).The absence of vascular invasion before treatment was found to be the best prognostic factor in the univariate analysis.Conclusions Sorafenib combined with transcatheter arterial chemoembolization and radiofrequency ablation is a promising approach to the treatment of large,unresectable hepatocellular carcinomas.However,large-scale randomized clinical trials are needed to determine the future role of this treatment.