The clinical evidence of applying programmed cell death-ligand 1 (PD-L1) inhibitors in the first-line setting to treat esophageal squamous cell carcinoma (ESCC) remains scarce. In this multicenter, randomized, double-blinded phase 3 trial, a total of 540 adults (aged 18-75 years) with unresectable, locally advanced, recurrent or metastatic ESCC who had not received systemic treatment were enrolled. All patients were randomized at 2:1 to receive sugemalimab (an anti-PD-L1 antibody; 1200 mg) or placebo every 3 weeks for up to 24 months, plus chemotherapy (cisplatin 80 mg/m2 on day 1 plus 5-fluorouracil 800 mg/m2/day on days 1-4) every 3 weeks for up to 6 cycles. At the prespecified interim analysis, this study has met its dual primary endpoints. With a median follow-up of 15.2 months, the prolongation of progression-free survival (PFS) was statistically significant with sugemalimab-chemotherapy compared with placebo-chemotherapy (median 6.2 v 5.4 months, hazard ratio [HR] 0.67 [95% confidence interval [CI] 0.54 to 0.82], P=0.0002) as assessed by blinded independent central review (BICR). Overall survival (OS) was also superior with sugemalimab-chemotherapy (median 15.3 v 11.5 months, HR 0.70 [95% CI 0.55 to 0.90], P=0.0076. A significantly higher objective response rate (60.1% v 45.2%) assessed by BICR was observed with sugemalimab-chemotherapy. The incidence of Grade 3 or above treatment-related adverse events (51.3% v 48.4%) was comparable between the two groups. Sugemalimab plus chemotherapy significantly prolonged PFS and OS in treatment-naïve patients with advanced ESCC, with no unexpected safety signal. This study is registered on ClinicalTrials.gov (NCT04187352).