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Xuegang Yang,1,2 Heping Deng,3 Yanyuan Sun,1 Yi Zhang,3 Yujie Lu,3 Guohui Xu,1,&ast; Xiaoqi Huang2,&ast; 1Department of Interventional Therapy, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Chengdu, People’s Republic of China; 2Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, Department of Radiology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 3Department of Radiology, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guohui Xu, Department of Interventional Therapy, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, 55 Renmin South Road 4th Section, Chengdu, Sichuan, 610041, People’s Republic of China, Tel +86-13708010123, Fax +86-02885420195, Email xgh0913@hotmail.com Xiaoqi Huang, Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, Department of Radiology, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, People’s Republic of China, Tel +86-18980605806, Fax +86-02885420195, Email julianahuang@163.comPurpose: We compare the efficacy and safety of regorafenib plus immune checkpoint inhibitors (ICIs) with transarterial chemoembolization (R+ICIs+TACE) versus regorafenib plus ICIs (R+ICIs) as the second-line treatment for patients with advanced hepatocellular carcinoma (HCC).Methods: This retrospective study included patients with advanced HCC who received R+ICIs+TACE or R+ICIs as the second-line treatment from January 2019 to April 2022. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs) were compared between the two groups. The propensity score matching (PSM) was used to reduce the influence of confounding factors on the outcomes. Factors affecting PFS and OS were analyzed using a Cox proportional-hazards regression model.Results: In total, 52 patients were included in this study, of whom 28 patients received R+ICIs+TACE and 24 patients received R+ICIs. After PSM (n=23 in each group), patients who received R+ICIs+TACE had a higher ORR (34.8% vs 4.3%, P=0.009), a longer PFS (5.8 vs 2.6 months, P< 0.0001), and a longer OS (15.0 vs 7.5 months, P=0.014) than those who received R+ICIs. Age ≤ 50 years old, Child-Pugh class A6 and B7, and R+ICIs were found as independent prognostic factors for poor PFS. R+ICIs, α-fetoprotein > 400 ng/mL, and platelet-to-lymphocyte ratio > 133 were noted as independent prognostic factors for poor OS. The difference in the incidence of TRAEs between the two groups was not statistically significant (P> 0.05).Conclusion: Compared to regorafenib plus ICIs, regorafenib plus ICIs with TACE was tolerated and improved survival as the second-line treatment for patients with advanced HCC.Keywords: advanced hepatocellular carcinoma, regorafenib, immune checkpoint inhibitors, transarterial chemoembolization, second-line treatment