OBJECTIVE: This study aims to compare the effectiveness and safety of TACE combined with molecular targeted therapy (MTT) plus Programmed death-ligand 1 (PD-(L)1) antibodies versus MTT plus PD-(L)1 antibodies for HCC patients. METHODS: Data from HCC patients who received either MTT plus PD-(L)1 (systemic therapy group) or TACE combined with MTT plus PD-(L)1 (combination therapy group) were retrospectively analyzed. The primary outcome was the objective reaction rate (ORR) at the initial assessment post-treatment initiation. Secondary outcomes included progressive free survival (PFS), overall survival (OS) and grade-3 or higher adverse events. RESULTS: A total of 222 HCC patients were included (109 in the systemic therapy group, 113 in the combination therapy group). Propensity score matching yielded 80 patients per group. The odds ratio for ORR in the combination therapy group was 1.29 (95% CI: 0.64–2.60; p=0.479). Subgroup analysis revealed significantly higher ORR for patients with AFP≤200 ng/mL in the combination therapy group (OR=3.54, p=0.016). For patients without PVTT, the ORR odds were slightly higher with combination therapy (OR=5.33, p=0.068). Multivariate Cox regression analysis showed no significant differences in PFS (HR=0.68, p=0.131) or OS (HR=0.86, p=0.674) between the two groups. Higher baseline AFP (>200 ng/mL) was associated with worse PFS (HR=1.68, p=0.012) and OS (HR=2.33, p=0.021). Surgical resection improved PFS (HR=0.42, p<0.001) and OS (HR=0.31, p=0.004). Grade 3 or higher adverse events were more common in the combination therapy group (52% vs 15%, p<0.0001). CONCLUSION: No significant benefits were observed for combining TACE with MTT and PD-(L)1 in unresectable HCC patients. However, TACE may offer advantages for patients with AFP≤200 ng/mL or without PVTT.