Background/Aims: Sufficient sedation is important when performing an endoscopic submucosal dissection (ESD) for an esophageal squamous cell carcinoma (ESCC), and dexmedetomidine (DEX) is being increasingly used. ESD is often performed in elderly patients and those with comorbidities. Therefore, adverse events (AEs) in the circulatory and respiratory systems remain a clinical concern.Despite this, limited data exist on these AEs, so this study was conducted to investigate this issue. Methods: This single-center retrospective study included 526 patients who underwent ESD for ESCC under DEX-based sedation from 2016 to 2023. The study assessed the incidence of AEs in circulatory and respiratory systems, as well as the risk factors associated with these events. Various clinical factors, including the Prognostic Nutritional Index (PNI), were analyzed as candidates. Results: Circulatory AEs occurred in 55 cases (10.5%), including bradycardia (7.2%) and hypotension (4.2%). Univariate and multivariate analyses revealed significant associations of lower PNI (<45) and prolonged procedure time with circulatory AEs (p=0.023 and p=0.008, respectively). Respiratory AEs occurred in 12 cases (2.3%), including respiratory depression (1.0 %) and post-ESD pneumonia (1.5 %) with one fatal case (0.2 %). An analysis of respiratory AEs showed that the elderly (≥80 years) and lower PNI were significant in univariate analysis but not in multivariate analysis (both p=0.07). Conclusions When performing ESD for ESCC under DEX-based sedation, special caution is needed for patients with lower PNI and the elderly, who are more likely to experience circulatory or respiratory complications.