Background: For >20 years, TACE has been a standard of care for embolization-eligible uHCC; however, most people with uHCC treated with TACE progress within 1 year. Embolization creates a proinflammatory tumor microenvironment and increases VEGF signals; clinical studies have established the role of immune checkpoint inhibitors (ICIs; e.g. D) and VEGF inhibitors (e.g. B) in advanced HCC. Methods: In EMERALD-1 (NCT03778957; double-blind, global, Phase 3 study), participants (pts) with embolization-eligible uHCC, Child-Pugh A to B7 liver function, Eastern Cooperative Oncology Group performance status 0–1, and no evidence of extrahepatic disease were randomized 1:1:1 to the D+B+TACE, D+TACE, or TACE arms. TACE was cTACE or DEB-TACE (investigator choice). Pts received D (1500 mg) or placebo for D (Q4W) plus TACE. After completion of last TACE, pts received D (1120 mg) or placebo for D plus B (15 mg/kg) or placebo for B (Q3W). Primary endpoint was progression-free survival (PFS) for D+B+TACE vs TACE. Secondary endpoints included PFS for D+TACE vs TACE, overall survival (OS), objective response rate (ORR), time to progression (TTP), and safety for D+B+TACE or D+TACE vs TACE. PFS, ORR, and TTP were assessed by blinded independent central review (RECIST v1.1). Results: In total, 616 pts with BCLC Stage A (25.8%), Stage B (57.3%), and Stage C (16.1%) were randomized to D+B+TACE (n=204), D+TACE (n=207), or TACE (n=205). Demographic and baseline characteristics were generally balanced across arms. At final PFS analysis, the primary objective was met: PFS significantly improved for D+B+TACE vs TACE (median [m]PFS 15.0 vs 8.2 months [mo]; hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.61–0.98; p=0.032 [threshold 0.0434]). Results were consistent across most prespecified subgroups. The secondary endpoint of PFS for D+TACE vs TACE was not statistically significant (mPFS 10.0 vs 8.2 mo; HR, 0.94; 95% CI, 0.75–1.19; p=0.638). ORR was 43.6%, 41.0%, and 29.6%, and mTTP was 22.0, 11.5, and 10.0 mo for D+B+TACE, D+TACE, and TACE, respectively. No new safety signals were identified. In the D+B+TACE (n=154), D+TACE (n=232), and TACE (n=200) safety analysis sets, respectively, 32.5%, 15.1%, and 13.5% of pts had maximum Grade 3/4 treatment-related adverse events (TRAEs); 8.4%, 4.3%, and 3.5% discontinued due to TRAEs; and 0%, 1.3%, and 2.0% died due to TRAEs. Pts continue to be followed for OS. Conclusions: D+B+TACE is the first ICI-based regimen in a global Phase 3 trial to show statistically significant and clinically meaningful improvement in PFS, vs TACE, in pts with embolization-eligible uHCC. Safety was manageable and consistent with the safety profiles of D, B, and TACE in uHCC. D+B+TACE has the potential to set a new standard of care in uHCC. Clinical trial information: NCT03778957.