AbstractObjectiveLenvatinib plus anti‐programmed death‐1 (anti‐PD‐1) antibody combinations have shown potent anti‐tumor effect in phase I/II trials in advanced or unresectable hepatocellular carcinoma (HCC), but real‐world data are limited.MethodsTo investigate the effectiveness and safety of lenvatinib plus anti‐PD‐1 antibodies in a real‐world cohort, we retrospectively evaluated 210 patients with unresectable or advanced HCC treated with these regimens between October 2018 and February 2022.ResultsThe objective response rate and disease control rate per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 were 28.1% and 75.2%. Median overall survival (OS) and progression‐free survival (PFS) in the overall cohort were 17.2 and 8.4 months, respectively. Median OS and PFS of patients receiving first‐line treatment reached 18.9 and 9.6 months. Median OS was significantly longer in patients with Child‐Pugh class A versus B (18.8 vs. 5.9 months, respectively), as was median PFS (9.1 vs. 4.4 months). Patients with albumin–bilirubin (ALBI) grade 1 versus grade 2/3 also had significantly greater median OS (23.5 vs. 13.4 months). Treatment‐related adverse events (AEs) occurred in 79.5% of patients. Patients with ALBI grade 2/3 had a higher rate of grade 3/4 AEs than patients with ALBI grade 1 (57.5% vs. 38.5%).ConclusionLenvatinib combined with anti‐PD‐1 antibody therapy was effective in patients with sufficient liver function reserve. Further study is needed to improve therapeutic efficacy and AE management in patients with Child‐Pugh class B or ALBI grade 2/3.