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Background Cadonilimab, a bispecific antibody simultaneously targeting programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4, may further boost antitumor activity compared with PD-1 or programmed cell death ligand 1 (PD-L1) inhibitors. Here, we evaluated the safety and efficacy of cadonilimab combined with chemotherapy as the first-line treatment in advanced esophageal squamous cell carcinoma (ESCC).Methods Treatment-naïve patients with unresectable locally advanced or metastatic ESCC were eligible. Cadonilimab combined with paclitaxel or nab-paclitaxel and cisplatin was administrated for up to six cycles, then cadonilimab monotherapy continued as maintenance until progressive disease or unacceptable toxicity, with a maximum of 24 months. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Plasma cell-free DNA samples were collected before and after treatment and prepared for DNA methylation level sequencing.Results As of September 27, 2024, 43 patients were enrolled with a median age of 61 years (range 44–75), 39.5% had PD-L1 combined positive score ≥10 and 95.3% had distant metastases. The ORR was 81.4% (95% CI 66.6% to 91.6%) and DCR was 97.7% (95% CI 86.2% to 99.9%). The median PFS was 7.10 months (95% CI 5.68 to 8.48) while OS remained immature. The mean pretreatment cytosine-phosphate-guanine (CpG) site methylation levels of APBA2, EPAS1, TRIM58, ITPKA and LINC00554 were significantly higher in responders than those in non-responders. Grade 3–4 treatment-related adverse events were reported in 53.5% (23/43) patients.Conclusions Cadonilimab combined with taxane and cisplatin as first-line treatment revealed encouraging antitumor activity and manageable safety in patients with advanced ESCC. DNA methylation level might be a potential biomarker for guiding patient outcomes.Trial registration number NCT05522894.