Background: Targeted drug therapy and transcatheter arterial chemoembolization (TACE) is the most effective control method for middle and late-stage hepatocellular carcinoma (HCC). Regorafenib as the second-line treatment of patients with advanced HCC, combined with TACE treatment still achieved good results in clinic. However, there is no relevant research at present. However, there is no relevant research at present. This study was to investigate the efficacy and safety of regorafenib combined with TACE in the treatment of patients with advanced HCC after the failure of first-line targeted treatment. Methods: Fifty-nine patients with advanced HCC received second-line regorafenib treatment between October 2019 and September 2021 were enrolled in the study. Patients were treated with routine TACE. Oral administration of regorafenib was started 1 week after the operation for 3 weeks and then stopped for 1 week. Objective response rate (ORR), disease control rate (DCR), median progression-free survival (m-PFS), and safety were evaluated according to the modified Response Evaluation Criteria in Solid Tumors (m-RECIST). In our study, most of the analyses are descriptive. Results: One patient achieved complete response (CR), and 24 patients achieved partial response (PR). stable disease (SD) was observed in 14 patients, while progression disease (PD) was observed in 20 patients. The ORR was 42.3% (25/59), and the DCR was 66.1% (39/59). The longest follow-up was 23 months, and the shortest was 1 month. Disease progression was found in 45 patients during follow-up. Among these patients, the longest interval before the detection of disease progression was 16 months, and the shortest was 1 month. Among patients who had disease progression, the median PFS was 8 months. Adverse events (AEs) were observed in 59 patients. These included hand-foot reaction (n=50, 84.7%), weight decrease (n=18, 30.5%), hypertension (n=8, 13.6%), proteinuria (n=1, 1.7%), weakness (n=12, 20.3%), diarrhea (n=1, 1.7%), and hoarseness (n=9, 15.3%). No treatment-related death occurred. Conclusions: Regorafenib combined with TACE achieved a good ORR and DCR among patients with advanced HCC receiving second-line targeted therapy, with only 9 patients experiencing grade 3 or 4 adverse reactions. Therefore, regorafenib combined with TACE is effective and safe in the treatment of advanced HCC.