Background: Previous studies proposed therapeutic synergy between loco-regional therapies and checkpoint inhibitors in hepatocellular carcinoma (HCC). We aimed to study the safety and efficacy of sequential transarterial chemoembolization (TACE) and stereotactic body radiotherapy (SBRT) followed by Avelumab in patients with locally advanced HCC. Methods: Patients with locally advanced HCC not suitable for curative resections were eligible. All patients had HCC ≥ 5cm, tumor nodules ≤3, and child-Pugh A5-B7 liver function. Tumors with distant metastasis, main portal vein (VP4) invasion, or inferior vena cava (VV3) invasion were excluded. Patients underwent single episode of TACE followed by 5-fraction SBRT (28 days afterwards), followed by Avelumab (10mg per kg) 14 days afterwards and every 2 weeks thereafter. The primary endpoint was percentage of patients amendable to curative surgery, defined as R0 resection with sufficient remnant liver volume and function. Secondary endpoints were objective response rate (ORR) per modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1, survivals, and treatment-related adverse event (TRAE). The sample size assumed that around 20% patients amendable to surgery after experimental treatment compared to 5% of historical institutional results after TACE. Modified Simon two-stage optimal design was used (power, 80%; a = 0.05; P0 = 0.05; P1 = 0.20; n1 = 10; n = 29 with an additional four patients to allow for drop-out or other reasons). Results: Out of 67 patients screened, 33 patients were enrolled. The median sum of diameter of lesion(s) was 15.1cm (range: 5.3-31.1cm), and 21 (63.6%) had marcrovascular invasion (n=13, hepatic vein, n=3 branched portal vein, n=5 both). After a median follow-up of 17.2 months (range: 3.5-31.6 months), 3 (9.1%) patients had tumor downstaged with curative surgery done. The objective response rate was 62.5% (95% CI, 45.3-77.1%), of whom 15 had complete response (CR) (43.8%) and 6 had partial response (18.7%). The median overall survival (OS) and progression-free survival was 30.3 months (95% CI: 22.7-37.8 months) and 20.7 months (95% CI: 14.6-26.8 months) respectively. All three patients with surgery done were alive at 2 years (100%). For 15 patients had CR, the 2-year OS rate was 92.9% without surgery. Ten patients (30.3%) experienced ≥ grade 3 TRAEs, commonly transient increase in alanine / aspartate aminotransferase (n=4, 12.1%) and bilirubin (n=2, 6%) level after TACE. Five patients (15.2 %) developed ≥ grade 3 immune-related adverse events. Conclusions: Although merely 9% of patients were downstaged to receive curative surgery, combined locoregional treatment and immunotherapy is safe and resulted in an unexpectedly high CR rate of 43% and median OS of 30 months in patients with locally advanced unresectable HCC. Clinical trial information: NCT 03817736.