BACKGROUND: The combination of regorafenib and immune checkpoint inhibitor (ICI) has been the most popular second-line systemic therapy for advanced hepatocellular carcinoma (HCC). However, considering the good anti-tumor performance of lenvatinib, combined immunotherapy on the basis of lenvatinib after first-line lenvatinib failure is also popular in clinical practice. This study aimed to compare the efficacy and safety of regorafenib plus ICI (TACE-R-I) versus lenvatinib plus ICI (TACE-L-I) in patients with advanced HCC after lenvatinib failure. METHODS: In this single-center retrospective study, 164 patients with advanced HCC were enrolled from January 2019 to March 2024 in China. All patients were aged ≥ 18 years, clinically or pathologically diagnosed with HCC. All patients received trans-arterial chemoembolization (TACE) as local treatment. Overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (TRAEs) were compared between groups. The Cox regression model was used to analyze the factors associated with OS and PFS. RESULTS: We compared 77 patients from each group after propensity score matching (PSM). There was no significant difference in the OS (p = 0.255) or PFS (p = 0.387) between groups. However, in the subgroup (distant metastases, Barcelona Clinic Liver Cancer (BCLC) stage C or tumor thrombus), the TACE-R-I group showed better survival benefit than the TACE-L-I group. The multivariable Cox regression model suggested that BCLC stage and alpha-fetoprotein (AFP) were independently associated with OS. Distant metastases, tumor thrombus and Child-Pugh were independent associated factors for PFS (p <
0.05). The frequency of grade ≥ 3 TRAEs was not significantly different between groups (p ≥ 0.05). CONCLUSION: Our study demonstrated that in patients with greater tumor burden, the TACE-R-I group showed better OS and PFS benefits than the TACE-L-I group. However, in the overall population of HCC patients, there was no significant difference in efficacy and safety between the groups.