Background: Surgical resection is one of the most effective treatments for HCC. However, the recurrence rate after hepatectomy is still very high with the 5-year recurrence rate of 60~70%, which is even higher in patients with high-risk recurrence factors. There is no globally recognized standard adjuvant therapy for HCC after radical resection. Here, we evaluated the safety and efficacy of donafenib combined with anti-PD-1 antibody as adjuvant therapy for HCC patients with high risks of recurrence. Methods: We retrospectively analyzed the patients who were diagnosed as hepatocellular carcinoma and underwent R0 resection in Chinese PLA general hospital from June 2021 to Nov 2022, and were confirmed by pathological examination to have any one of the following high-risk factors: the number of tumors ≥ 2, the maximum diameter of tumors ≥ 5cm, portal vein tumor thrombus, microvascular invasion (MVI) and satellite lesions. These patients would receive donafenib combined with anti-PD-1 antibody as adjuvant therapy up to 1 year. The primary endpoint was recurrence free survival (RFS). Secondary endpoints included 1 and 2 year RFS rate, overall survival (OS) and safety. Results: 32 patients were included in this analysis, all of them received donafenib 100mg bid plus anti-PD-1 antibody as adjuvant therapy. Pts were classified as BCLC stage A (50.0%), B (15.6%) and stage C (34.4%). The study population was predominantly HBV-positive (87.5%). 17/32 (53.1%) pts had microvascular invasion, 8/32 (25%) had satellite nodules and 2/32 (6.3%) had portal vein tumor thrombus. 17/32 (53.1%) pts had tumor size ≥5 cm, the median tumor size was 5.00 cm (range 2.0 to 12.5) based on pathological findings and 8/32 (25%) had tumor number≥2. Seven pts (21.9%) underwent secondary surgery after tumor recurrence, the rate of tumor rupture and incomplete capsules were 9.4% and 18.8% respectively. 1 patient (3.1%) had bile duct tumor thrombus. The median duration of follow up was 7.34 months, three pts experienced recurrence and one patient died of liver failure. The 1-year recurrence-free survival rate was 80.1%. The median RFS was 18.62 months (95%CI, 7.33 to 29.91). The median OS was not reached. Among all the pts who received adjuvant therapy, 27 (84.4%) pts had at least one treatment-related AE (TRAE). Grade 3 TRAEs occurred in 4 (12.5%) pts, no grades 4 or 5 were reported. 1 (3.1%) patient discontinued treatment because of high risk of upper gastrointestinal bleeding. Common TRAEs included hand-foot syndrome (28.1%), platelet count decreased (25.0%), aspartate aminotransferase increased (21.9%), rash (18.7%) and blood bilirubin increased (15.6%). Conclusions: The combination of donafenib and anti-PD-1 antibody as adjuvant therapy demonstrated promising efficacy and was well tolerated in HCC patients with high risks of recurrence.