BACKGROUND: This trial aimed to compare the outcomes of drug-eluting beads transarterial chemoembolization (DEB-TACE) with CalliSpheres microspheres (CSM) and conventional transarterial chemoembolization cTACE in the treatment of patients with unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: A total of 90 patients were divided into DEB-TACE group (n = 45) and cTACE group (n = 45). The treatment response, overall survival (OS), progression-free survival (PFS), and the safety were compared between the two groups. RESULTS: The objective response rate (ORR) in the DEB-TACE group was significantly higher than that in cTACE group at 1, 3, and 6 months of follow-up ( = 0.031, = 0.003, = 0.002). The complete response (CR) in DEB-TACE group was significantly higher than that in cTACE group at 3 months ( = 0.036). Survival analysis revealed that, DEB-TACE group had better survival benefits than cTACE group (median OS: 534 days . 367 days, = 0.027; median PFS: 352 days . 278 days = 0.004). The degree of liver function injury was more serious in DEB-TACE group at 1 week, but was similar between the two groups at 1 month. DEB-TACE with CSM caused a high incidence of fever and a severe abdominal pain ( = 0.031, = 0.037). CONCLUSIONS: DEB-TACE with CSM showed better treatment response and survival benefits than cTACE group. Although a transient more severe liver damage, high incidence of fever and a severe abdominal pain occurred in the DEB-TACE group, it could be resolved through symptomatic treatment.