To investigate the efficacy and safety of dicycloplatin as chemotherapeutic regimen in transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC).In this randomized, open-label, phase II trial, patients with unresectable HCC who were TACE treatment-naïve or experienced recurrence after surgical resection or ablation were enrolled at 7 centers in China from March 2019 to November 2019. Participants were randomly assigned (1:1:1) to receive TACE with chemotherapeutic regimen of dicycloplatin alone (group A1), dicycloplatin plus epirubicin (group A2), or epirubicin alone (group B). The primary endpoint was objective response rate (ORR). The secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and safety.The ORR at 6 months in group A1 (n = 22) was significantly better than that in group B (p = 0.093; 90% confidence interval [CI], 1.03-9.45). The DCR in group A1 was significantly higher than that in group B (p = 0.045; 90% CI, 1.29-12.88). There was no significant difference in DOR among the groups (p = 0.271). The median PFS were 6.00 and 3.05 months in groups A2 (n = 25) and B (n = 24), respectively (p = 0.061). Grade 3 or worse adverse events were similar among groups in the safety population (p = 0.173).TACE with dicycloplatin was comparably safe and well tolerable as epirubicin alone in patients with unresectable HCC. Compared with epirubicin alone, significant improvement in ORR and DCR when dicycloplatin was applied, as well as prolonged PFS when dicycloplatin plus epirubicin was applied, was generated.• To our knowledge, this is the first multicenter randomized trial to assess the efficacy and safety of TACE with dicycloplatin in patients with unresectable HCC. • This phase II trial showed that TACE with dicycloplatin alone or plus epirubicin was comparably safe and well tolerable as epirubicin alone. • Significant improvements in ORR, DCR when dicycloplatin was applied, and prolonged PFS when dicycloplatin plus epirubicin was applied were recorded compared with epirubicin alone.© 2022. The Author(s), under exclusive licence to European Society of Radiology.