Endoscopic submucosal dissection (ESD) for superficial esophageal squamous cell carcinoma (ESCC) is performed for the treatment of lesions with varied backgrounds and factors. However, the predictive factors associated with the technical difficulty of ESD remain unknown in patients with varied lesions. Therefore, this study aimed to identify the predictive factors associated with the technical difficulty of ESD for ESCC using a retrospective cohort. This multicenter, retrospective study was conducted in 10 hospitals in Japan. Consecutive patients who underwent esophageal ESD between January 2013 and December 2019 were enrolled. Lesions of subepithelial tumors, adenocarcinoma, and adenoma were excluded. Difficult lesions were defined as ESD requiring a long procedure time (≥120 min), perforation development, piecemeal resection, or discontinued ESD. In the present study, the clinical factors were assessed to identify the technical difficulty of ESD using univariate and multivariate analyses. Among 1708 lesions treated with esophageal ESD, eight subepithelial tumors, 44 adenocarcinomas, and two adenomas were excluded. Finally, 1505 patients with 1654 lesions were analyzed, and 217 patients with 217 lesions (13.1%) were classified as patients with difficult lesions. In multivariate analysis, the predictive factors associated with the technical difficulty of ESD were as follows: tumors with varices, tumors with diverticulum, antiplatelet use (discontinued), circumference of tumor (≥1/2), preoperative tumor size ≥30 mm, trainee, and nonhigh-volume center. This multicenter retrospective study identified the predictive factors associated with the technical difficulty of ESD for ESCC with varied backgrounds and factors.