PURPOSE: Programmed death ligand 1(PD-L1)/programmed cell death-1(PD-1) inhibitors have shown promising efficacy in unresectable patients with advanced hepatocellular carcinoma (HCC), but the results are not consistent. Our goal was to evaluate the safety and efficacy of PD-L1/PD-1 inhibitors or plus anti-CTLA-4 antibody or anti-VEGF agents for the treatment of unresectable HCC. METHODS: Cochrane library, Embase, and PubMed were searched till August 2021. Data on progression-free survival (PFS), objective response rate (ORR), overall survival (OS), and disease control rate (DCR) were pooled and analyzed by Stata14 software. RESULTS: Thirteen prospective trials with 2,386 HCC patients were included. Pooled analysis estimated an ORR of about 0.21 (95% CI = 0.18-0.25) and a DCR of 0.59 (95% CI = 0.52-0.65) for anti-PD-1/PD-L1 therapy. Summary PFS was 4.19 (95% CI = 3.31-5.18) months and summary OS was 13.23 (95% CI = 12.06-14.41) months. After using PD-L1/PD-1 inhibitors plus anti-VEGF agents, ORR was 0.26 (95% CI = 0.20-0.33), DCR was 0.75 (95% CI = 0.69-0.81) and PFS was 6.2 (95% CI = 4.61-7.78) months. PD-L1/PD-1 inhibitors plus anti-CTLA-4 antibody therapy achieved an ORR of 0.23 (95% CI = 0.14-0.33), an DCR of 0.44 (95% CI = 0.39-0.50) and a PFS of 1.88 (95% CI = 1.51-2.26). CONCLUSIONS: PD-L1/PD-1 inhibitors were effective and tolerable in patients with advanced HCC. Furthermore, compared with anti-PD-1/PD-L1 monotherapy, PD-L1/PD-1 inhibitors plus anti-VEGF agents resulted in more clinical improvements in ORR, DCR, and PFS.