Purpose To assess the efficacy and safety of drug-eluting beads transarterial chemoembolization (DEB-TACE) in liver cancer patients with different times of previous conventional transarterial chemoembolization (cTACE) treatments. Methods 367 liver cancer patients about to receive DEB-TACE treatment were enrolled in this prospective cohort study. All patients were divided into no previous cTACE group (NPC group), 1–2 times previous cTACE group (PC group) and triple or above previous cTACE group (TPC group) according to the times of previous cTACE treatments. Results There was no difference in complete response (CR) ( P  = 0.671) and objective response rate (ORR) ( P  = 0.062) among three groups. Additionally, no difference in overall survival (OS) among groups ( P  = 0.899) was found. As to liver function, most liver function indexes were deteriorative at 1 week after DEB-TACE operation, but returned to baseline at 1–3 months after DEB-TACE operation in all three groups, while percentage of abnormal total bile acid (TBA) patients was higher in TPC group than NPC and PC groups at 1–3 month post-DEB-TACE ( P  = 0.018). As for safety profiles, the incidence of pain during DEB-TACE operation was lower in TPC group compared to NPC and PC groups ( P  = 0.005), while no difference of other adverse events was found during and 1 month post-DEB-TACE treatment among three groups. Conclusion DEB-TACE treatment was equally efficient and tolerated in liver cancer patients with different times of previous cTACE treatments.