Background: The combination of atezolizumab and bevacizumab (Atezo-Bev) has become the standard first-line therapeutic regimen for patients with unresectable hepatocellular carcinoma (uHCC), while the therapeutic effect is limited in patients with high-risk characteristics (vp3/vp4 portal vein tumor thrombus or high tumor burden). Locoregional therapy plays an important role in minishing tumor burden and synergistic antitumor effect with systemic therapy, including transarterial embolization (TAE) and hepatic arterial infusion chemotherapy (HAIC). Herein, this study aimed to assess the efficacy and safety of atezolizumab and bevacizumab combined with TAE and HAIC in unresectable hepatocellular carcinoma with high tumor burden. Methods: This retrospective study reviewed the medical records of patients who had primary uHCC with high tumor burden (maximum nodule diameter >8 cm) receiving Atezo-Bev plus TAE and HAIC from September 2019 to September 2022 in our medical center. HAIC involved oxaliplatin, fluorouracil and leucovorin (FOLFOX regimen). Progression-free survival (PFS), overall survival (OS), tumor response according to mRECIST, and treatment-related adverse events (AEs) were evaluated. Results: In total, 30 patients were included in this study with a median follow-up period of 11.4 months. Twelve patients (40%) died and all the remaining patients reached the end point of PFS at the cut-off follow-up time. The median PFS of the 30 evaluable patients was 6.8 months (95% CI, 2.6-11.1 months), and the survival rates at 3 months, 6 months, 9 months, and 12 months were 86.2%, 82.5%, 68.6%, and 60%, respectively, and the median OS was not estimated (NE). According to the mRECIST, the objective response rate (ORR) was 74.4% (95% CI, 59.3%-89.5%), and the disease control rate (DCR) was 93.3% (95%CI, 85.4%-98.6%) respectively. Extrahepatic metastasis was an independent risk factor associated with PFS.As for the safety, there was no treatment-related mortality throughout the study period. The most common AEs were fever (6.7%), and diarrhoea(6.7%), and grade 3/4 AEs occurred among 6 patients (20%). Conclusions: Atezo-Bev combined with TAE and HAIC may be safe and effective for uHCC patients with high tumor burden, while further prospectively clinical research is necessary to validate the efficacy and safety.