Objective: This study aims to assess the efficacy and safety of penpulimab (a humanized anti-PD-1 IgG1 antibody) with anlotinib in the first-line treatment of Chinese patients with uHCC.Methods: In this open-label multicenter phase Ib/II trial, patients with histologically or cytologically confirmed uHCC, without previous systemic treatment, aged 18-75 years old, classified as BCLC stage B (not amenable for locoregional therapy) or C, with Child-Pugh score & LE;7 and ECOG performance status & LE;1 were enrolled. Patients received penpulimab [200 mg intravenous (i.v.) Q3W] and oral anlotinib (8 mg/day, 2 weeks on/1 week off). The primary endpoint was objective response rate (ORR). Secondary endpoints included safety, disease control rate (DCR), progression-free survival (PFS), time to progression (TTP), duration of response (DoR), and overall survival (OS). This trial is registered with ClinicalTrials.gov (NCT04172571).Results: At the data cutoff (December 30, 2020), 31 eligible patients had been enrolled and treated with a median follow-up of 14.7 months (range, 1.4-22.1). The ORR was 31.0% (95% CI, 15.3-50.8%), and the DCR was 82.8% (95% CI, 64.2-94.2%). The median PFS and TTP for 31 patients were 8.8 months (95% CI, 4.0-12.3) and 8.8 months (95% CI, 4.0-12.9) respectively. The median OS was not reached; the 12-month OS rate was 69.0% (95% CI, 48.9-82.5%). Only 19.4% (6/31) of patients had grade 3/4 treatment-related adverse events (TRAEs).Conclusion: Penpulimab plus anlotinib showed promising anti-tumor activity and a favorable safety profile as first-line treatment of patients with uHCC.