OBJECTIVES There is little information on the risk factors for hepatocellular carcinoma (HCC) and outcome of treatment with an all-oral combination of direct-acting antiviral regimens following eradication of hepatitis C virus (HCV) RNA. METHODS The study subjects were 1,170 patients with HCV genotype 1-related chronic liver disease treated with either NS5A inhibitor plus NS3/4A protease inhibitor (n = 707), NS5A inhibitor plus NS5B polymerase inhibitor (n = 345), or NS5A inhibitor, NS3/4A protease inhibitor plus ritonavir (n = 118), for 12-24 weeks. All patients were free of HCC before and during therapy. RESULTS In this retrospective study, 22 patients developed HCC during the follow-up (time from the end of antiviral therapy until the last visit: 1.3 years). At 1 and 2 years after completion of the treatment, the cumulative HCC rates for the whole group were 1.8 and 2.3%, respectively, and 1.4 and 1.8%, respectively, for 1,065 patients who showed sustained virological response (SVR). The risk factors for HCC identified by multivariate analysis were hypoalbuminemia, thrombocytopenia, a high α-fetoprotein level, and non-SVR for all patients, and hypoalbuminemia and a high α-fetoprotein level for patients with SVR. CONCLUSION Eradication of HCV RNA by direct-acting antiviral regimens might reduce the risk of HCC. Albumin and α-fetoprotein levels are significant risk factors for HCC.