e16133 Background: Based on the different anti-malignant mechanisms of tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs) and transarterial therapy, several studies have demonstrated the potential of combining these three treatments to improve outcomes in patients with unresectable hepatocellular carcinoma (uHCC). This study aimed to evaluate the efficacy and safety of transarterial therapy plus donafenib and ICIs for uHCC patients in a real-world setting. Methods: This multicenter retrospective study included patients with uHCC who had received at least one cycle of transarterial therapy (hepatic arterial infusion chemotherapy, HAIC, or transarterial chemoembolization, TACE) and donafenib and ICIs (anti-PD-1 available in China) at five cancer centers. Other key inclusion criteria were: (1) no prior systemic treatment; (2) at least one follow-up image data. The primary endpoint was progression-free survival (PFS) according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Secondary endpoints included overall survival (OS), objective response rate (ORR) and toxicity. Results: Of the 61 eligible patients enrolled, 56 (91.8%) were men, 54 (88.5%) had HBV infection, 26 (42.6%) had AFP level > 400 ng/mL, 38 (62.3%) were at BCLC stage C, 32 (52.5%) had macrovascular invasion, 14 (23.0%) had extrahepatic metastasis, 47 (77.0%) had multiple tumors and the median maximum tumor size was 86.0 mm (IQR, 61.5–122.6). Four kinds of ICIs were employed, including tislelizumab (n = 29), camrelizumab (n = 21), sintilimab (n = 9), toripalimab (n = 2). Up to the date of November 24, 2023, the median follow-up time was 13.0 months. The median PFS was 12.7 months (95%CI, 8.4–NA), with a 1-year PFS rate of 52.7% (95%CI, 37.9%–73.1%). The median OS was not reached, and 1-year OS rate was 88.4% (95%CI, 79.9%–97.8%). The ORR according to mRECIST was 70.5%. Twelve (19.7%) patients had received conversion resection, and the median conversion time was 3.1 months (95%CI, 2.37–NA). Overall, 51 (83.6%) patients experienced at least one treatment-related adverse events (TRAEs), 22 (36.1%) had grade 3 or 4 AEs, and no patients died due to AEs. The most common AEs greater than 15% were hand-foot skin reaction (47.5%), liver dysfunction (27.9%), decreased platelet count (19.7%) and hypoalbuminemia (16.4%). Conclusions: This retrospective real-world study showed that transarterial therapy combined with donafenib plus ICIs in the treatment of uHCC patients was well tolerated and comparable clinical efficacy to other triple therapies. This combination strategy may be an appropriate treatment option for uHCC patients.