Background: Transarterial chemoembolization (TACE) is widely applied and shows good efficacy in advanced hepatocellular carcinoma (HCC). Recently, hepatic arterial infusion chemotherapy (HAIC) has also gained popularity in the treatment of HCC. Several studies have described the comparison between HAIC and TACE or TACE combined with HAIC. However, the evaluation between TACE plus HAIC and HAIC is rarely reported. Here, we observed the performance of HepaSphere DEB-TACE combined with HAIC (Hepa-HAIC) comparing to HAIC in patients with advanced HCC. Methods: 167 patients diagnosed as advanced HCC and treated in Peking University Cancer Hospital from May 2018 to May 2022 were enrolled in this retrospective study, composed of 74 patients received HepaSphere DEB-TACE combined with HAIC-FOLFOX (Hepa-HAIC) and 93 patients received HAIC-FOLFOX. More than 60% patients experienced other treatments before the enrollment. To avoid the selection bias, propensity score matching (PSM) was conducted and applied for the efficacy and safety analysis between these two cohorts. The primary endpoints are progression-free survival (PFS) and overall survival (OS); the secondary endpoint includes objective response rate (ORR), disease control rate (DCR) and safety. Results: Propensity-matching yielded 48 pairs and the baselines were almost equal in Hepa-HAIC and HAIC cohorts after matching. Median PFS and median OS were both higher in matched Hepa-HAIC cohort (median PFS:8.9 vs. 5.8 months, P=0.035; median OS:22.4 vs. 9.5 months, P=0.027), which were consistent with pre-matching analysis. The ORR in Hepa-HAIC and HAIC cohorts was 75.0% and 37.5%, respectively; DCR was 93.8% after Hepa-HAIC and 81.3% after HAIC. There was no treatment-related death. Serious adverse events were similar in these two groups, except alanine aminotransferase (ALT) and vomiting. There was more frequency of Grade 3–4 ALT elevation in Hepa-HAIC (33.3% vs. 8.3%, P=0.003) while more incidence of vomiting in HAIC group (29.2% vs. 12.5%, P=0.044). Conclusions: All of the observed PFS, OS, ORR and DCR in Hepa-HAIC group are superior to HAIC group, which indicates the combination of HepaSphere DEB-TACE and HAIC may lead to improved outcomes with comparable safety profile in advanced HCC.