Objective The aim of the study was to assess the effectiveness and safety of a combined therapy with transcatheter arterial chemoembolization (TACE) and FOLFOX4, in patients with unresectable advanced hepatocellular carcinoma (HCC).Methods In this study, patients with advanced HCC, that received treatment between November 2015 and October 2017, were recruited. Among these, 30 patients were treated with TACE only (TACE group); whereas 33 patients were treated with a combination of FOLFOX4 chemotherapy and TACE (combination group). Survival analyses, including overall survival (OS) and progression free survival (PFS) analysis, were performed for both groups. Following this, the responses of patients to treatment were evaluated every 3 months, and the toxic and adverse events were observed. Results The median follow-up time was 9.2 months (3–36 months). In the combination group, at 3 months, a disease control rate (DCR) of 60.6％, and a median OS of 9.1 months was obtained [95％ confidence interval (CI) 6.5–11.7]. In the TACE group, the DCR and OS were 33.3％ and 5.5 months (95％ CI 4.3–6.7), respectively. On the other hand, the PFS in the combination and TACE groups were observed as 5.6 months (95％ CI 3.6–7.6) and 2.6 months (95％ CI 2.0–3.2), respectively. Both these findings indicate a statistically significant difference (P = 0.01) between both the groups. Similar TACE associated adverse events were observed in both groups. In the combination group, frequently observed FOLFOX4 related adverse effects included nausea (90.9％), leukopenia (75.8％), thrombocytopenia (69.7％), and vomiting (69.7％). Most adverse reactions were between grades I–Ⅲ and were alleviated after symptomatic treatments. Conclusion The combination of TACE with FOLFOX4 therapy has better effectivity and safety than TACE alone.