Background and study aims Duodenal endoscopic submucosal dissection (ESD) is still considered technically challenging; however, few studies have objectively analyzed predictors of the technical difficulty. Therefore, the aim of the current study was to elucidate predictors of the technical difficulty of duodenal ESD. Patients and methods This was a retrospective observational study. From June 2010 to June 2017, a total of 174 consecutive patients with superficial duodenal epithelial neoplasia who underwent ESD were included in this study. We tried to identify predictors for technical difficulty of ESD by defining technical difficulty as either procedure time > 100 minutes or intraprocedural perforation. Moreover, we constructed a scoring system consisting of factors that were significant in the multivariate analysis. Results The proportion of patients with technical difficulty was 34.5 %. In the multivariate analysis, lesion location in flexural part [odds ratio (OR), 2.61; 95 % confidence interval (CI), 1.02 - 6.68], larger lesion size (> 40 mm) (OR, 5.26; 95% CI, 2.15 - 12.9), and occupied circumference > 50 % of the duodenum (OR, 5.80; 95 % CI, 1.83 - 18.4) were associated with technical difficulty. Conclusion A lesion location in flexural part, lesion size >40 mm and occupied circumference > 50 % were risk factors for technical difficulty of duodenal ESD.