Background: The efficacy of first-line ICIs combination therapy patients with advanced hepatocellular carcinoma (HCC) was better than that of TKIs alone. This study was conducted to explore whether regorafenib combined with ICIs has better efficacy in second-line therapy. Methods: This retrospective study included 101 patients who have received regorafenib after the failure of at least one molecular-targeted therapy evaluated between March 2017 to November 2021. The patients were divided into two groups based on receiving regorafenib (cohort A) or regorafenib combined with ICIs(cohort B). The primary endpoint was Progression-Free Survival (PFS), and the secondary endpoints included the Objective Response Rate (ORR), Disease Control Rate (DCR), Overall Survival (OS), and safety. Results: 29 patients were in the cohort A and 72 were in the cohort B. There were no significant differences in age, gender, weight, ECOG performance status, Child-Pugh, BCLC staging, and the proportion of previous therapy regimens between the two cohorts. Among them, the first-line therapy mainly includes sorafenib, lenvatinib with or without ICIs. The median PFS (4.0 months), 6 months PFS rate (25.66%) and DCR(65.52%) of cohort A were poor than that of cohort B (8.7 months, 83.33%, 74.13%), (P＜0.05). OS data was not yet available. First-line therapy, use of TKI with ICIs (n = 31) or TKI without ICIs(n = 27) (PFS 8.70m VS 8.37m，P = 0.84), use of sorafenib with or without ICIs (n = 22), or lenvatinib with or without ICIs (n = 33)(PFS 8.87m VS 7.60m，P = 0.77), didn’t affect the PFS and ORR of the later line therapeutic regimens. In the cohort B, the ORR of the second-line (29.31%) was better than that of the third-line (0), (P = 0.03). Adverse events (AEs) of all grades were statistically different between the two groups (P = 0.03), but there was no significant difference in the incidence of grade 3-4 AE. Conclusions: In the later-line therapy, regorafenib combined with ICIs therapy showed better curative effect, especially in the second-line. Regorafenib combined with ICIs is recommended as early as second-line therapy to benefit patients. Different regimens of first-line therapy have no effect on PFS in second-line therapy.