Sorafenib is the most widely used multikinase inhibitor in patients with advanced hepatocellular carcinoma (HCC). Despite its efficacy, only a small proportion of patients experience tumor regression. Hepatic artery infusion chemotherapy (HAIC) can be used as an alternative treatment for HCC.A total of 139 patients with advanced HCC, treated with HAIC (HAIC group, n = 95) or sorafenib (sorafenib group, n = 44), were retrospectively analyzed in a single hospital. We compared the efficacy and overall survival (OS) between the 2 groups, and investigated the factors affecting response rate in the HAIC group.The objective response rate (ORR) was significantly higher in the HAIC group than in the sorafenib group (23.2% vs 2.3%; P = .01). The progression-free survival time was longer in the HAIC group than in the sorafenib group (274 vs 166 days; P = .03). However, there was no significant difference in OS between the 2 groups (359 vs 223 days; P = .05). In the multivariate analysis, international normalized ratio (INR), serum bilirubin, and presence of objective response were significant prognostic factors associated with OS (P = .03, P = .01, and P = .01, respectively). In the HAIC group, INR, nonobjective response group, and < 4 HAIC cycles were identified as independent risk factors of OS (P = .03, P = .01, and P = .01, respectively).The ORR in patients treated with HAIC was found to be superior to that in advanced HCC patients treated with sorafenib. Better tumor response and prolonged OS can be expected in patients who receive ≥ 4 HAIC cycles.