Background: Atezo-Bev is the standard first-line therapy against uHCC. However, there is no globally established subsequent treatment after failure on first-line Atezo-Bev. We aimed to evaluate the efficacy and safety of second-line regorafenib in uHCC pts who progressed on first-line Atezo-Bev. Methods: This is a phase II investigator-initiated trial involving 2 academic centers in Korea. Key eligibility criteria include confirmed diagnosis of HCC; prior treatment with Atezo-Bev at least ≥ 2 cycles; Child-Pugh A; ECOG performance status 0-1. Eligible patients received regorafenib 160 mg once daily 3 weeks on/1 week off until progressive disease or intolerable toxicity. The primary endpoint is progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR) according to the RECIST v1.1, overall survival (OS) and treatment-related adverse event (TRAE). Results: Total 40 pts were recruited from Dec 2021 to May 2023. Pts characteristics were as follows: median age of 56 (range, 36-81); hepatitis B (77.5%), hepatitis C (10.0%), non-viral (12.5%); BCLC C stage (97.5%); and AFP ≥ 400 ng/ml (40.0%). As of the date of data cut-off (15 Aug 2023), the median follow-up duration was 6.6 mo (95% CI, 5.0-8.2). The median PFS was 3.5 mo (95% CI, 3.0-4.0). ORR and DCR were 10.0% and 82.5%. The median OS was 9.7 mo (95% CI, 8.3-11.1) and 6-month OS rate was 55.0%. The median OS since the start of prior Atezo-Bev was 16.6 mo (95% CI, 11.9-21.3). When stratified according to the duration of prior Atezo-Bev (<4 cycles [n=10] vs. ≥4 cycles [n=30]), pts with ≥4 cycles of prior Atezo-Bev showed better median OS (not reached vs 3.6 mo; p=0.001) and ORR (13.3% vs 0%; p=0.009), while there was a trend for better median PFS (3.8 mo vs 2.5 mo; p=0.107). The most common grade 3-4 TRAEs were thrombocytopenia (5.0%), palmar-plantar erythrodysesthesia (2.5%), and fatigue (2.5%). Conclusions: Regorafenib was effective as second-line therapy in uHCC pts who progressed on first-line Atezo-Bev. Efficacy and safety outcomes from our study were consistent with those observed in the pivotal phase 3 RESORCE trial which included sorafenib-tolerated/progressed pts. Clinical trial information: NCT05134532.