Objective: Patients with hepatocellular carcinoma (HCC) have a high risk of recurrence after liver resection, and finding effective adjuvant therapy is crucial for improving patient prognosis. The efficacy of transcatheter arterial chemoembolization (TACE) combined with targeted therapy has attracted attention, but there is still insufficient research on its comparison with TACE alone. The aim of this study is to compare the efficacy differences between adjuvant TACE combined with targeted therapy and TACE alone in patients with high risk of recurrence of hepatocellular carcinoma after surgery, and to evaluate the impact of the two treatment regimens on patient survival and recurrence. Methods: This study is a retrospective cohort study that analyzed the prognosis of adjuvant TACE combined with targeted therapy in high-risk hepatocellular carcinoma patients with postoperative recurrence between January 2014 and December 2022. The patients were divided into two groups, one receiving adjuvant TACE combined with targeted therapy, and the other receiving simple TACE treatment. Collect clinical data, treatment plans, and follow-up results of patients, and compare the survival and recurrence rates of two groups of patients. The main research endpoints include overall survival (OS) and recurrence free survival (RFS), and comparisons are made between groups. Apply the COX proportional hazards regression model to conduct univariate and multivariate analyses of OS and RFS, respectively. Result: After adjustment for confounding factors, multivariable analysis identified that TACE + targeted therapy was independently associated with better OS (HR: 0.47; 95% CI: 0.30-0.74; P = 0.001) and RFS (HR: 0.40; 95% CI: 0.20-0.80; P = 0.010) in patients with HCC at a high risk of recurrence after hepatectomy. In addition, BCLC stage-C, Child-Pugh grade B, preoperative extrahepatic metastasis, and surgical margin > 1cm were independent risk factors of OS for patients with HCC at a high risk of recurrence after hepatectomy. Meanwhile, BCLC stage-C, tumor differentiation (moderate versus poor), and preoperative extrahepatic metastasis were independent risk factors of RFS for patients with HCC at a high risk of recurrence after hepatectomy. Conclusion: By analyzing and comparing the prognostic outcomes of adjuvant TACE combined with or without targeted therapy in high-risk hepatocellular carcinoma patients with postoperative recurrence, this study found that adjuvant TACE combined with targeted therapy had a better prognosis than TACE alone: median OS and median RFS were longer. The combination of adjuvant TACE and targeted therapy is an independent influencing factor for better OS and RFS, respectively.