e16242 Background: Currently, more than 55% of liver cancer patients have recurrence within 1 years after radical surgery. However,there is no standard treatment of neoadjuvant therapy for resectable HCC patients. This study aimed to explore the efficacy and safety of the triple therapy [Tislelizumab combined with lenvatinib plus transcatheter arterial chemoembolization (TACE)] as neoadjuvant therapy in patients with resectable HCC with high-risk of recurrence. Methods: This prospective, single-arm, phase II trial (ChiCTR2200059574) enrolled patients with primary resectable HCC who had not received prior anti-tumor therapy. The recurrence rate was predicted to be > 50% according to the risk predictor ( http://www.asapcalculate.top/Cal2_ch.html ) of early recurrence before surgery. TACE will be performed once on Day 1. Tislelizumab (an anti-PD-1 antibody, 200 mg) intravenously once every 3 weeks and lenvatinib (body weight ≥ 60 kg, 12 mg;< 60 kg, 8 mg) orally daily was initiated 3 days after TACE treatment. Surgery was performed after two cycles of neoadjuvant treatment. After 4-6 weeks of surgery, patients continued to receive tislelizumab and lenvatinib for 6 months to 1 year. Primary endpoint was adverse events (AE) and major pathological reactions. Secondary endpoints were objective response rate (ORR) by mRECIST, relapse-free survival (RFS) and overall survival (OS). Results: From April 2022 to August 2023, 19 patients (median age, 55 years) were enrolled, all Child-Pugh A and ECOG PS 0, mostly males (89.5%) and HBV infection (94.7%). According to mRECIST, the ORR was 94.7% (18/19, CR 2, PR 16), and the DCR was 94.7% too (18/19, CR 2, PR 16, SD 0). In 19 patients, 14 patients had received surgical treatment (R0 resection rates were 100%), 12 patients (12/14, 85.7%) achieved major pathological reaction (necrosis≥90%), and 2 patients (2/14, 14.3%) achieved complete pathological response. For those patients who did not undergo surgery, 3 of them refused surgery, and 2 patients lost the chance of surgery because of disease progression and high ICG R-15, respectively. At the end of the last follow-up (January 20, 2024), tumor recurrence was detected in 2 patients after surgery. The 12-month RFS rate and OS rate were 80.2%(95% CI: 40.4%-94.8%)and 94.7%(95% CI: 68.1%-99.2%), respectively. Median RFS and OS were not reached. No grade 3 or above AE were observed. Conclusions: Tislelizumab, lenvatinib, and TACE were safe and showed promising efficacy as a neoadjuvant therapy for resectable HCC with high risk of recurrence. Clinical trial information: ChiCTR2200059574.