Background: Anti-angiogenic plus anti-PD-1/L1 agents have shown superior efficacy over sorafenib in the first-line treatment for uHCC. Anlotinib, a multi-targeted tyrosine kinase inhibitor that targets VEGFR 1/2/3, FGFR 1-4, PDGFR α and β, and c-kit. Toripalimab is a humanized lgG4 mAb against PD-1. Preliminary results exhibited promising efficacy and tolerable safety of the combined regimen. Here we reported the updated results at the data cutoff of August 24, 2022. Methods: This single arm, multicenter, phase II trial of ALTER-H003 was planned to enroll 30 eligible pts to receive anlotinib (12mg, p.o., qd, d1-14, q3w) and toripalimab (240mg, iv, d1, q3w) until disease progression or unacceptable toxicity. Primary endpoint was ORR. Secondary endpoints included PFS, OS, DCR, DoR and safety. Results: From Jan, 2020 to Jul, 2021, 31 pts were enrolled. Pts characteristics were as follows: median age of 56y (range: 27-75); hepatitis B (29, 93.5%); BCLC B/C (23, 74.2%/8, 25.8%); macrovascular invasion (11, 35.5%); extrahepatic metastasis (19, 61.3%) and AFP>400 ng/ml (12, 38.7%). The median follow-up time was 19.9m (95%CI: 14.3–25.5). The confirmed ORR and DCR by mRECIST was 32.3% (95%CI: 14.8-49.7%) and 77.4% (95%CI: 61.8-93.0%), respectively. 10 pts achieved tumor response and the mDOR was 11.1m. The median PFS was 11.0m (95%CI: 3.5-18.4) and the median OS was 18.2m (95%CI: 15.9-20.5). Grade 3-5 treatment-related adverse events (TRAEs) were recorded in 20 pts (64.5%). The common ≥ grade 3 TRAEs included hand-foot skin reaction (3, 9.7%), hypertension (3, 9.7%) and impaired liver function (3, 9.7%). 2 pts had an irTRAE (pneumonitis; impaired liver function) that led to death. Conclusions: Anlotinib plus toripalimab showed hopeful efficacy and manageable toxicity in the first-line treatment for uHCC. Further studies are warranted. Clinical trial information: ChiCTR1900028295.