Background: Conversion therapy achieve tumor downstaging and provide middle-advanced stage HCC patients with opportunities for radical resection. Lenvatinib combined with immune checkpoint inhibitors (ICIs) and FOLFOX-HAIC has shown high conversion success rates. This study aimed to evaluate the efficacy and safety of tislelizumab combined with lenvatinib and FOLFOX4-HAIC as first-line conversion therapy in this population. Methods: Between April, 2021, and April, 2022, we retrospectively analyzed clinical data of HCC patients with BCLC stage B or C who underwent tislelizumab combined with lenvatinib and FOLFOX4-HAIC. The primary outcome included objective response rate (ORR), disease control rate (DCR), conversion resection rate (CRR) and treatment-related adverse events (TRAEs). Data were expressed as median(range). Results: A total of 18 patients (17 male, 1 female) completed conversion therapy assessment until the last follow-up time (December 27, 2022). The patients were characterized with a median age of 55.5 years (37-72), body mass index 24.9(19.8-33.9), 1 patient with BCLC stage B, 16 patients with BCLC stage C, and 1 patient with HCC postoperative recurrence with intrahepatic metastasis. According to mRECIST criteria, tumor shrinkage was observed in all patients, with an ORR of 94.4% (17/18, including 61.1% [11/18] complete response), DCR of 94.4% (17/18), and median time to response(mTTR) of 1.4 months (0.7-3.0). Successful conversion was observed in 11 (61.1%) of 18 patients per mRECIST. As of cut-off date, the actual CRR and pathological complete response(pCR) were 38.9% (7/18) and 57.1% (4/7), respectively. No surgical deaths occurred, and at the last follow-up review, there was disease free survival in all patients after operation. With a follow-up time of 20.7 months, median progression-free survival (PFS) and overall survival (OS) were not reached, with a 3- and 6-month progression-free survival rate of 94.4% and 83.3%. During the follow-up period, 6 patients developed disease progression with a median time to progression (mTTP) of 5.4 months (1-6.7), of whom 3 died due to disease progression. Most common TRAE was aspartate aminotransferase (AST) increased (16 patients, 88.9%). Grades ≥3 TRAEs occurred in 12 patients (66.7%), with only one grade 4 TRAE (AST increased). All TRAEs were tolerable and manageable. Conclusions: Tislelizumab combined with lenvatinib and FOLFOX4-HAIC showed high conversion rate and acceptable toxicity in the treatment of middle-advanced stage HCC, suggesting that this combination could be considered as a new conversion strategy in this population.