Objectives To compare efficacy and safety of super-selective DEB-TACE with doxorubicin-loaded microspheres sized below and above 100 microns for treatment of hepatocellular carcinoma (HCC). Material and methods All consecutive patients with HCC who underwent DEB-TACE were included in this retrospective study. Regarding to microsphere size (>100 microns or <100 microns), patients were determined as Group A (n = 28) and Group B (n = 30), respectively. Results Of the 58 patients (78% males), no statistically significant difference was found between the two groups in terms of age and gender (P = 0.388, P = 0.888, respectively). There were no significant differences between the two groups in terms of BCLC stages, presence of chronic liver disease, and Child-Pugh classes (P = 0.593, P = 0.081, P = 0.391, respectively). Although statistically insignificant, median overall survival (19 months vs 32 months, P = 0.190) and median progression-free survival (13 months vs 20 months (P = 0.574) were longer and 1-3-years objective response rates (7.40% vs 23.33%, P = 0.330) were higher in Group B than in Group A, respectively. No mortality or major complications were observed. Grade I/II adverse events were detected in all patients. Transient elevations in liver function tests (Grade III adverse events) were similar in both groups (3.57% vs 3.33%; P = 0.980). Conclusion Super-selective DEB-TACE with doxorubicin-loaded microspheres sized <100 microns is an effective and safe method for the HCC treatment. Objective response rates are higher and survival durations are longer after DEB-TACE performed with doxorubicin-loaded microspheres sized below 100 microns.