Abstract Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. A first-line standard of care, sorafenib results in median overall survival of 12 months in patients with Child-Pugh class A disease and 6 months in patients with Child-Pugh class B disease with objective response rates (ORRs) not exceeding 19%. These low efficacy rates have driven research on alternative therapeutic options, particularly immune-checkpoint inhibitors (ICIs). We reviewed the response rates (estimated by RECIST 1.1 criteria) across patients with advanced HCC treated with ICIs in phase I–IV clinical trials published between December 2012 to December 2020; 17 reports were identified as eligible and included in the quantitative analysis. Within the selected studies, pembrolizumab + lenvatinib reached the highest absolute ORR (36%), with first-line atezolizumab + bevacizumab showing the second highest ORR (27.3%). With regard to second-line therapy, nivolumab + ipilimumab reached an ORR of 32%, and pembrolizumab alone resulted in an ORR of 17% among sorafenib-experienced patients with advanced HCC. In summary, current studies show high response rates of ICIs in patients with advanced HCC. Nonetheless, further studies are required in the second-line setting to further evaluate ICI therapeutic superiority. Finally, it is of particular interest to examine the therapeutic potential of ICIs for patients with decompensated liver disease (Child-Pugh class C), currently not eligible for any systemic therapy. Implications for Practice Immune-checkpoint inhibitors (ICIs) can provide high objective response rates (ORR, estimated with RECIST 1.1. criteria) when used as first-line treatment in advanced hepatocellular carcinoma, particularly pembrolizumab + lenvatinib (ORR 36%) or atezolizumab + bevacizumab (ORR 27.3%). In sorafenib-experienced patients, nivolumab + ipilimumab (ORR 32%) provided the highest ORR among ICI-based regimens. These findings emphasize high therapeutic potential of ICI-based therapies in patients with advanced hepatocellular carcinoma, although further studies are required to further validate and define their role in this context.