Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death. Surgical resection remains as the mainstay of curative treatment option, However, the recurrence rate after surgical resection could be high especially in patients with CNLC stage IIb (tumor number ≥ 4) and IIIa (vascular invasion). Herein we evaluated the efficacy and safety of the anti-angiogenic tyrosine kinase inhibitor, anlotinib, plus TQB2450, a novel programmed death-ligand 1 (PD-L1) inhibitor as an adjuvant treatment for HCC with high risk of recurrence after radical resection. Methods: This prospective, multiple-center, single-arm phase II study (NCT05111366) enrolled histologically confirmed resectable HCC pts for CNLC Stage IIb/IIIa with any of the following high-risk factors for recurrence: a) tumor nodules ≥4; b) portal vein tumor thrombus (PVTT): vp1 or vp2; c) hepatic vein tumor thrombus (HVTT): vv1 or vv2. At 4-8 weeks after R0 resection, adjuvant therapy was started with anlotinib (12 mg, p.o., qd, d1-14, q3w) plus TQB2450 (1200 mg, i.v., d1, q3w) until disease recurrence or unacceptable toxicity or up to 18 cycles (~1 year). Primary endpoint was 1-year recurrence-free survival (RFS) rate; secondary endpoints were RFS, 1-year overall survival (OS) rate, and safety. Results: Between January 2022 and August 2023, a total of 22 pts from 4 centers were enrolled, 21 pts included in per-protocol set analysis. The 21 pts were predominantly male (95 %, n = 20), and the median age was 50 years (range: 33–75). Eight pts (38%) had CNLC Stage IIb and 13(62%) had CNLC Stage IIIa HCC. Among them, 19 pts received at least once tumor assessment. According to RECIST 1.1, out of 21 pts, 16 showed no recurrence, 3 relapsed, 1 dropped out and 1 discontinued due to serious adverse events. The 1-year RFS rate was 62.31%（95%CI: 17.15-88.08）, while the median RFS was not mature. Additionally, safety profile exhibited that the regimen was tolerable. 16 of 22 pts (73%) experienced treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 6 pts (27 %) including hypertension (13.5 %), neutropenia (9 %), and bleeding (4.5 %). Conclusions: The present study indicated that anlotinib plus TQB2450 as adjuvant treatment for HCC with high risk of recurrence after radical resection exhibited potential efficacy and tolerable safety profile. The conclusion should be validated in more participants included subsequently. Clinical trial information: NCT05111366.