Background: Regorafenib and PD-1 inhibitor both are recommended as the standard second-line treatment for advanced hepatocellular carcinoma (HCC) in currently authorized guidelines. Local interventional therapies showed significant benefits in the treatment of HCC. We aimed to evaluate to investigate the efficacy and safety of regorafenib + PD-1 inhibitor combined with intervention therapy as the second-line treatment option for advanced HCC. Methods: From October 2019 to February 2022, 31 patients with advanced HCC treated with regorafenib+PD-1 were retrospectively included. All patients were divided into two groups: group A (n = 17, patients received regorafenib +PD-1 combined with local therapy), and group B (n = 14, patients received regorafenib+PD-1). The inclusion criteria are as follows: the first-line treatment was sorafenib or lenvatinib; advanced HCC (BCLC-C); ECOG score was 0-1; Child-Pugh score was 5-7; at least one measurable lesion; expected survival time ≥ 3 months. The treatment efficacy was evaluated by modified-RECIST. Objective response rate (ORR) and disease control rate (DCR) were evaluated in two groups. Major complications referred to those that result in death or serious adverse effects including sepsis, uncontrollable bleeding, and acute renal failure; others were considered minor complications. Results: The median follow-up time was 12.9 months. The median PFS was 8.3 months vs. 7.5 months (p = 0.814). The median TTP (Time to Progression) time was 8.3 months vs. 7.5 months (p = 0.973). In group A, eleven patients received TACE, 2 received thermal ablation, and 4 received HAIC. In group A: four patients reached PR (Partial response), and 7 patients stayed SD (Stable disease), while six patients suffered tumor progression (PD, Progression disease); In group B, only one patient reached PR, and 7 patients stayed SD, 6 patients suffered tumor progression. The ORR was 23.5% (group A) vs. 7.1% (group B), respectively. The DCR was 64.7% (group A) vs 57.1% (group B), respectively. The daily dose of Regorafenib was 80mg (58.8%), 120mg (29.4%), and 160mg (11.8%), respectively in group A. The daily dose of Regorafenib was 80mg (57.1%), 120mg (28.5%), and 160mg (14.3%), respectively in group B. The dose for the PD-1 inhibitor was 200mg (every three weeks). Adverse events of systemic drugs in group A and group B were 58.8% (10/17), and 35.7% (5/14), respectively. Hand–foot skin reaction was the most common adverse event in both groups (47.1% (8/17) vs 35.7% (4/140), respectively). No major complications of local therapies were observed in both groups. Conclusions: Regorafenib+PD-1 combined with local therapy as the second-line treatment option for advanced HCC may be effective and safe and provides better benefits than regorafenib+PD-1 alone.