Background: The combination of anti-angiogenesis and immune checkpoint blockade showed promising outcomes for advanced HCC. Hepatic artery infusion chemotherapy (HAIC) combined with apatinib and camrelizumab could augment treatment efficacy in preliminary study. But HAIC had disadvantages such as technical limitations, expensive cost and poor patient comfort. In the present study, we aimed to investigate the efficacy and safety profile of VIC with apatinib and camrelizumab for CNLC stage Ⅲ HCC. Methods: This single-arm, phase II study enrolled treatment-naive adult (18 years) patients(pts) with CNLC stage Ⅲ and Child-Pugh score small or equal to 7 points (NCT05412589). Eligible pts received VIC (oxaliplatin 85 mg/ m², leucovorin 200 mg/m², 5-fluorouracil bolus 400 mg/m² on day 1, and 5-fluorouracil infusion 2400 mg/m² for 46 hours; q3w; 6 cycles), combined with apatinib (250 mg qd) and camrelizumab (200 mg q3w). The primary endpoint was objective response rate (ORR) per RECIST 1.1. Following an optimal Simon 2-stage design, 15 eligible pts needed to be included in the 1st stage, of whom at least 9 pts had to achieve objective responses to warrant further investigation in the second stage. Secondary endpoints were progression-free survival (PFS) rate at 6 months, PFS, overall survival (OS) per RECIST v1.1 or mRECIST, and safety. Results: At the data cut-off date (Jan. 31,2023), 17 pts were enrolled from Apr. 25, 2021, to Oct. 30, 2022 (1 woman and 16 men; median age, 48 years; 16 had HBV infection). The median tumor size was 87 mm. 11 (64.7%) pts had more than 3 tumors. 8 (47%) pts had main portal trunk invasion (Vp4). 7 (41.2%) pts had distant metastasis. The median follow-up was 8.17 months and all pts had at least one post-baseline tumor assessment. The confirmed ORR was 58.8% with 10 partial responses (PR) per RECIST v1.1, which met the threshold for expanding enrollment, while 70.6% per mRECIST. Among them, 11 (64.7%) pts received operation successfully and 5 (29.4%) pts reached pathological complete response (pCR). Notably, four pCR pts had Vp4 before the trial. The disease control rate was 94.11% whether per RECIST v1.1 or mRECIST. The median time to response was 2.27 months (interquartile range (IQR), 1.29-2.56) per RECIST v1.1 or 1.57 months (IQR, 1.17-2.32) per mRECIST. The estimated 6-month PFS rate was 76.4% per RECIST v1.1. The 6-month OS rate were 100%. Grade 3-4 treatment-related adverse events (AEs) occurred in 56.2% of pts, of which the most common were decreased neutrophils (38.5%), diarrhea (23.9%), thrombocytopenia (25.9%), and hypertension (11.1%). All AEs were expected and manageable, and no treatment-related deaths were reported. Conclusions: The triplet treatment of VIC plus camrelizumab and apatinib showed promising antitumor activity and acceptable safety for CNLC stage Ⅲ HCC, especially in those with main portal trunk invasion. Clinical trial information: NCT05412589.