Background The treatment of huge hepatocellular carcinoma (HCC) is still challengeable due to its deteriorative heterogeneity, for which conventional transarterial chemoembolization (TACE) is proposed as an efficient therapy; however, drug-eluting beads TACE (DEB-TACE) is rarely reported in these patients. Thus, the current study aimed to explore the efficacy, prognostic factors, and safety of DEB-TACE using CalliSpheres in huge HCC patients. Methods Ninety-nine huge HCC patients treated by DEB-TACE using CalliSpheres were retrospectively reviewed. Treatment response, change of tumor markers, liver function indexes, progression-free survival (PFS), and adverse events were retrieved. Results Objective response rate (ORR) was 66.1%, 48.6%, and 23.8%, then disease control rate (DCR) was 85.5%, 67.6%, and 33.3% at month (M) 1, M3, and M6, respectively; furthermore, carcinoembryonic antigen (CEA) (p = 0.037), alpha fetoprotein (AFP) (p < 0.001), and protein induced by vitamin K absence or antagonist-II (PIVKA-II) (p < 0.001) were all declined at 1 month after DEB-TACE. The median PFS was 8.3 (95% confidence interval: 6.0-10.6) months with 1-year and 2-year PFS rates of 38.5% and 15.5%, accordingly. Moreover, elevated China liver cancer (CNLC) stage (p = 0.036, hazard ratio (HR): 1.937) and abnormal cancer antigen 199 (p = 0.019, HR: 2.465) were correlated with unfavorable PFS. Besides, liver function indexes were not deteriorated after DEB-TACE. Lastly, main adverse events included pain (20.2%), fever (17.2%), nausea (14.1%), and vomit (9.1%), which were mild and manageable. Conclusion DEB-TACE using CalliSpheres presents satisfying efficacy and tolerable safety in huge HCC patients, suggesting that it might be a good treatment option for these patients.