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 60̃70%, which is even higher in patients with high-risk recurrence factors (the cumulative 1-year recurrence rate was about 50% without intervention). Here investigators intended to explore the safety and efficacy of donafenib combined with anti-PD-1 antibody as adjuvant therapy for HCC patients with high risks of recurrence. Methods: In this single-center study, eligible HCC patients with high-risk recurrence factors after radical surgery were recruited to receive donafenib combined with anti-PD-1 antibody for six months. The starting dose of donafenib was 100 mg PO BID in the first six patients and then reduced to 100 mg PO QD at the investigator’s discretion on tolerability in the adjuvant setting. For patients who started with donafenib 100 mg QD, the dose could be escalated to 100 mg BID from the second 21-day cycle if there were no experience grade ≥2 major adverse reactions (i.e. hand-foot syndrome, abnormal liver or kidney function, and blood cell decreased) reported in cycle 1. The primary endpoint was the cumulative 1-year recurrence-free survival rate. The secondary endpoints were recurrence-free survival (RFS), overall survival, quality of life (QoL) measured with FACT- Hepatobiliary questionnaire, and adverse events (AEs). Results: Between June 2020 and December 2021, thirteen patients with BCLC stage A-B HCC were enrolled. 11/13 (84.6%) patients had microvascular invasion (8 w/ M1 and 3 w/ M2). 11/13 (84.6%) patients had one tumor. 4/13 (30.8%) patients had tumor size ≥5 cm and 4/13 (30.8%) had satellite nodules. The median tumor size was 3.00 cm (IQR 2.60 to 6.00) and 3.29 cm (IQR 2.20 to 6.50) based on pathological findings and image, respectively. Eleven patients were included in efficacy analysis (two were excluded due to ineligibility). The median duration of follow-up was 8.30 months (IQR 2.90-14.40). Two patients experienced recurrence. The cumulative 1-year recurrence-free survival rate was 80% (90%CI, 49% to 93%). The median RFS was not reached. QoL showed a trend of improvement after 9 weeks of treatment. Among all the patients who received donafenib plus anti-PD-1 antibody, grade 3 treatment-related AEs (TRAEs) occurred in 7/13 (53.8%) patients (no grades 4 or 5 were reported). Common TRAEs included alanine aminotransferase increased (53.8%), aspartate aminotransferase increased (53.8%), blood bilirubin increased (38.5%), white blood cell decreased (38.5%), platelet count decreased (38.5%), rash (38.5%). No deaths were reported. Conclusions: The combination of donafinib and anti-PD-1 antibody as adjuvant therapy was well tolerated and demonstrated promising efficacy in HCC patients with high risks of recurrence. Clinical trial information: NCT04418401.