Objective:To evaluate the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined with tislelizumab and tyrosine kinase inhibitor (TKI) as a conversion therapy in patients with initially unresectable hepatocellular carcinoma (HCC).Methods:The clinical data of 51 initially unresectable HCC patients admitted to the Department of Hepato-Pancreato-Biliary Surgery, the Eighth Affiliated Hospital of Guangxi Medical University from March 2022 to November 2023 were prospectively collected, including 46 males and 5 females, aged (53±11) years old. All patients received TACE combined with tislelizumab and TKI. For initially unresectable HCC patients who have successfully undergone conversion therapy, surgical resection was performed sequentially. Follow-up was conducted through regular outpatient visits or hospitalization combined with telephone contact, and the surgical conversion, relapse-free survival and adverse reactions of patients were recorded.Results:Among the 51 patients with initial unresectable HCC, there were 12 cases of stage Ib, 14 cases of stage IIa, 10 cases of stage IIb, and 15 cases of stage IIIa in Chinese liver cancer staging. The 51 patients were evaluated according to the modified solid tumor response evaluation criteria, and 15 patients had complete response, 26 had partial response, 5 had stable disease, and 5 had disease progression. The objective response rate was 80.4% (41/51), and the disease control rate was 90.2% (46/51). The conversion success rate was 49.0% (25/51), 2 patients gave up surgery, and the actual conversion rate was 45.1% (23/51). Among the 23 patients who underwent surgical resection, irregular hepatectomy was performed in 11 cases, lobectomy in 8 cases, and hemihepatectomy in 4 cases. Common treatment-related adverse events were hand-foot syndrome, hypertension, gingival bleeding, etc. Most of the drug-related adverse events were grade 1 to grade 2. A total of 10 patients (19.6%, 10/51) had grade 3 drug-related adverse events, and no grade 4 or above adverse events occurred, and no treatment-related deaths occurred. The cumulative recurrence free survival rates of 23 patients with initial unresectable HCC at 6 and 12 months after sequential hepatectomy were 100% and 94.7% respectively.Conclusion:The triple combination therapy of TACE combined with tislelizumab and TKI in the treatment of initial unresectable HCC has good clinical efficacy, and the adverse reactions are safe and controllable.