Background: Sequential transarterial chemoembolization and stereotactic body radiotherapy followed by immunotherapy (IO) (START-FIT) using anti-PD-L1 has demonstrated promising efficacy in locally advanced HCC (laHCC). We aimed to evaluate START-FIT activity using anti-PD-L1 and anti-CTLA-4 IO backbone. Methods: Adult patients with laHCC not suitable for curative resections were recruited. Each with tumor at least 5cm, maximum three tumors, and child-Pugh A5-B7 liver function. Patients had single TACE, 5-SBRT 28 days after, then single Tremelimumab (300mg) and regular 4-week interval Durvalumab (1500mg) at 7 days upon SBRT completion. Primary endpoint was overall response rate (ORR) per modified Response Evaluation Criteria in Solid Tumors (mRECIST); secondary endpoints included progression-free survival (PFS), overall survival (OS), and treatment-related (TR) adverse event (AE) [NCT04988945]. Results: During 11 Dec, 20 and 3 Oct, 22, 16 patients were enrolled with median age 66 (range (r): 51–84 years), 14 (87.5%) were male, the lesion(s) diameter median sum was 11.2 cm (r: 5.8–15cm), and 11 (68.8%) had macrovascular invasion (n=6, hepatic vein, n=4, branched portal vein, n=1 both). With median 11.3 months (r: 3.7–24.5 months) follow-up time, the best ORR was 81.3% (95% CI: 54.4–96.0%) (Complete response CR: n=7, 43.8%; partial response PR: n=6, 37.5%; static disease SD + progressive disease PD: n=3, 18.7%). The 6 and 12-month PFS rates was 86.7% (95% CI: 69.3–100%) and 58.7% (95% CI: 33.6–84.4%), while 6 and 12-month OS rates was 100% (95% CI: 91.7–100%) and 83.3% (95% CI: 62.2–100%) respectively. The 12-month OS with CR vs. PR vs. SD+PD was 100%, 75%, and 50% respectively. Four (25%) and one patient (6.3%) experienced TRAEs and immune-related AE of grade 3 or worse respectively. Conclusions: START-FIT using STRIDE is safe and effective in unresectable laHCC resulted in 43.8% CR rate and promising survival. Clinical trial information: NCT04988945.