4103 Background: The combination of immune checkpoint blockade and multikinase inhibitor has been proven to improve clinical outcomes of advanced HCC. Hepatic arterial infusion chemotherapy is an intra-arterial procedure that has been widely used in Asia, with high response rate. The aim of this trial was to evaluate the efficacy and safety of HAIC combined with tislelizumab and lenvatinib for initial unresectable HCC with portal vein tumor thrombus (PVTT). Methods: This is a prospective, single-arm phase II study. Patients with histologically or cytologically diagnosed or clinically confirmed hepatocellular carcinoma and accompanied by PVTT, no previous systemic treatment were eligible for inclusion. Patients received HAIC(FOLOFOX), combined with intravenous tislelizumab (200mg, q3w) and lenvatinib (8/12mg, qd) for six cycles, followed by maintenance therapy with tislelizumab and lenvatinib until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per RECIST 1.1 and mRECIST. Results: Between Sep, 2021 to Nov, 2023, a total of 29 eligible patients were enrolled and evaluable for efficacy analyses: median age 54 years (M/F:25/4; CNLC stage IIIa/IIIb: 24/ 5). Portal vein tumor thrombus PVTT Ⅰ-Ⅱ/PVTT Ⅲ-Ⅳ:19/10. An average of 4.35 times of HAIC were underwent in these patients. With a median follow-up of 11 months (interquartile range [IQR] 7.5-21.5), the confirmed ORR was 68.97% (95%CI 49.19-84.72)and 58.62%(95%CI 38.94-76.48)per mRECIST and RECIST v1.1, respectively. The disease control rate (DCR) according to mRECIST and RECIST v1.1 were both 93.10% (95%CI 77.23-99.15). Median progression-free survival (PFS) was 15 months (95%CI 10-22). Median overall survival (OS) was not reached. 7(24.1%) patients became eligible for surgical resection. 1 of them received surgical resection and was confirmed as pathological CR; 6 of them refused surgical treatment and received tislelizumab and lenvatinib treatment continuously. 27(93.1%) patients had mild treatment related adverse events (TRAEs) (grade 0-2). Common TRAEs included hypoproteinemia (93.10%), abdominal pain (72.41%), nausea (68.97%) and leukopenia (65.52%). There were no deaths due to TRAEs. Conclusions: HAIC (FOLOFOX) combined with tislelizumab and lenvatinib afforded promising efficacy and safety in tumor control in patients with advanced HCC with PVTT in short-term observation and an eligible surgical conversion rate was observed. Clinical trial information: CHiCTR2100051717.