PURPOSE: CalliSpheres microspheres (CSM) are the first drug-eluting beads (DEB) developed in China. This study aimed to compare treatment response, survival, and safety profiles between DEB transarterial chemoembolization (DEB-TACE) with CSM and conventional TACE (cTACE) in huge hepatocellular carcinoma (HCC) patients. METHODS: A total of 71 patients with huge HCC who underwent DEB-TACE or cTACE were consecutively enrolled in this retrospective cohort study. Treatment response was assessed at first month (M1), third month (M3), and sixth month (M6) after TACE therapy; progression-free survival (PFS) and overall survival (OS) were evaluated; liver function indexes were recorded before TACE operation (M0), at first week (W1), M1 and M6 after TACE therapy; adverse events which occurred after TACE operation were recorded. RESULTS: DEB-TACE presented with higher objective response rate (60.0% vs. 29.7%, < 0.05) and disease control rate (86.7% vs. 59.4%, < 0.05) compared with cTACE at M3. Regarding survival profiles, PFS [median: 3.3 months (95% CI: 2.8-3.7) vs. 2.1 months (95% CI: 1.7-2.5)] as well as OS [median: 7.8 months (95% CI: 4.6-11.0) vs. 5.7 months (95% CI: 5.0-6.3)] were longer in DEB-TACE group compared with cTACE group (both < 0.01). Multivariate Cox's regression further illustrated that DEB-TACE vs. cTACE was an independent protective factor for PFS and OS (both < 0.01). As for safety profiles, patients' liver function injury was reduced in the DEB-TACE group compared with the cTACE group. The incidence of fever was lower, and CINV was less severe in the DEB-TACE group compared with the cTACE group (both < 0.05), while no difference in occurrence of liver abscess, increase of ascites, or moderate pain between two groups was observed. CONCLUSION: DEB-TACE with CSM presents with better treatment response, survival profiles, as well as safety profiles compared with cTACE in treatment for huge HCC patients.