Background: Transarterial chemoembolization (TACE) is the preferred therapeutic regimen for patients with intermediated-stage (BCLC-B stage) unresectable hepatocellular carcinoma (uHCC). However, selected patients with high tumor burden have shown improved survival with systemic treatment, including targeted therapy, immunotherapy, or combination of them. This study was to evaluate the efficacy and safety of combination therapy for BCLC-B stage uHCC beyond up to seven criteria. Methods: In total, 120 patients enrolled in the study during 2015-2021, which were divided into 3 groups according to receive different treatment, and each group just comprised 40 patients. One group received treatment with TACE only (T group), and the other two groups received TACE combined with Lenvatinib (T+L group) and TACE combined with Lenvatinib and tislelizumab (T+L+P group) respectively. We retrospectively compared the clinical outcomes including overall survival (OS), progression-free survival (PFS) and tumor response among the three groups. Both PFS and tumor response were based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Besides, adverse events were collected to assess the safety as well. Results: The median duration of follow-up for all the patients was 28 months [95% CI, 22.8-34.2 months]. The median OS (mOS) was 24.2 months among patients in T+L+P group, as compared with15.0 months among patients receiving TACE alone (HR 0.32; 95%CI 0.19-0.55; P<0.001). The mOS was 20.6 months in T+L group (HR in comparison with TACE only, 0.54; 95%CI 0.34-0.85; P=0.008). The mOS was longer in T+L+P group comparing with T+L group (HR 0.49; 95%CI 0.29-0.85, P=0.011). The similar median PFS (mPFS) benefit was also detected among 3 groups (T+L+P vs. T HR 0.35; 95%CI 0.21-0.58; P<0.001. T+L vs. T HR 0.57; 95%CI 0.36-0.90; P=0.007. T+L+P vs. T+L HR 0.53; 95%CI 0.33-0.84; P=0.003). There was no significant statistic difference observed in objective response rate (ORR) and disease control rate (DCR) between each two groups (P>0.05). Grade 3 or 4 adverse events (AEs) occurred more common in T+L group or T+L+P group, which was mainly due to target-related or immune-related AEs. There was no mortality happened related to treatment. Conclusions: TACE combined with lenvatinib and tislelizumab may significantly improve clinical outcomes both compared with TACE alone and TACE combined with lenvatinib with a manageable safety profile for BCLC-B stage uHCC beyond up to seven criteria. Nevertheless, it is necessary to be validated by means of prospective randomized control studies in future.