Background: The therapeutic strategy for recurrent hepatocellular carcinoma (HCC) after hepatectomy is limited. There is a significantly unmet clinical need for effective treatment options for these patients. This study aimed to assess the clinical efficacy and safety of regorafenib alone or combined with a PD-1 inhibitor as a second or further-line treatment for patients with recurrent HCC after hepatectomy. Methods: Patients receiving regorafenib alone or combined with a PD-1 inhibitor in Peking University People’s Hospital from January 2019 to November 2022 were entered prospectively into a clinical database. Data were retrospectively analyzed. The major inclusion criteria were: histologically confirmed diagnosis of HCC; disease recurrence after radical hepatectomy; with tumor that cannot be re-resected; ECOG performance status score (PS) ≤2. Regorafenib was administered at the daily dose of 80-120 mg for more than 4 weeks. Progression-free survival (PFS) was the primary endpoint. The second outcomes included PFS, objective response rate (ORR), disease control rate (DCR), and the incidence of drug-related adverse events (AEs). CTCAE v5.0 was used for evaluation of AEs. Results: Twenty-two patients were enrolled with a median age of 59. The hepatic function of all patients was mildly impaired (Child-Pugh A). Among all patients, 36.35% of cases were enrolled in Barcelona Clinic Liver Clinic (BCLC) A and the remainder were in BCLC B. Eight cases (36.36%) received regorafenib in combination with PD-1 inhibitor therapy and 14 cases received regorafenib treatment alone. Among all patients, 86.36% of the cases were treated with regorafenib as second-line therapy. Five patients (22.73%) had extrahepatic metastasis. The median PFS and overall survival (OS) were 11.66 (±10.20) months and 16.92 (±10.21) months, respectively. The 3-month PFS rate was 100%. The 6-month and 12-month PFS rates were 75% (95%CI: 58.49%-96.70%) and 53.33% (95%CI: 34.88%-81.50%), respectively. The results showed a significant difference in median PFS between patients receiving regorafenib as second-line therapy and third-line therapy [12.30 months (95%CI: 4.25-20.36) vs 4.30 months (95%CI: 3.50-5.10); P<0.001]. In addition, there is a significant difference in median PFS between patients with extrahepatic metastasis and those without extrahepatic metastasis [5.20 months (95%CI: 3.48-6.92) vs 18.20 months (95%CI: 5.09-31.31; P=0.003)]. The ORR and DCR were 18.18% and 81.82%. The most frequent AEs were hand-foot syndrome (40.91%), pain (18.18%), diarrhea (13.64%), and hypertension (13.64%). Most AEs were grade 1 or 2, with only 1 case having grade 3 AE. Conclusions: Regorafenib alone or combined with a PD-1 inhibitor showed significant clinical efficacy in controlling the disease progression of recurrent HCC.