Background: Centrally located hepatocellular carcinoma (HCC) is a subtype HCC with special location adjoined hepatic portals. It is difficult to be radically resected with sufficient surgical margin. We discussed whether neoadjuvant therapy could increase surgical margin and reduce recurrence. Methods: From January 2018 to September 2023, 106 centrally located HCC patients who underwent radical liver resection were retrospectively included. Neoadjuvant therapy included transarterial chemoembolization (TACE) with programmed death 1 (PD-1) inhibitors plus tyrosine kinase inhibitor (TKI). Surgical margin and long-term outcomes were compared between patients with and without neoadjuvant therapy. Results: 40 patients underwent neoadjuvant therapy and 66 patients underwent surgery alone. In neoadjuvant therapy group, 3 (7.5 %) patients achieved progression disease, 9 (22.5 %) patients achieved stable disease, 13 (32.5 %) achieved partial response and 15 (37.5 %) achieved complete response based on the mRECIST criterion. Ultimately, 36 patients (90 %) underwent subsequent surgical resection in the neoadjuvant therapy group. The neoadjuvant therapy had the advantages of declining alpha fetoprotein level (5.9 ng/mL vs 50.1 ng/mL, P = 0.001), microvascular invasion rate (MVI) (12.5 % vs 30.3 %, P = 0.036), reducing tumor size to 5.1 +/- 2.1 cm from 6.2 +/- 2.2 cm (P = 0.021), and increasing more patients with surgical margin>1 cm (30.0 % vs 7.6 %, P = 0.002). The neoadjuvant therapy group reduced tumor recurrence and prolonged overall survival. Multivariate analysis found that neoadjuvant therapy was an independent protective factor for overall survival and recurrence free survival.<br /> Conclusions: Neoadjuvant therapy showed advantage of reducing tumor burden and increasing surgical margin for centrally located HCC, resulting in longer overall survival and recurrence free survival.