Objective: To identify risk factors for tumor positive resection margins after neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy for esophageal cancer. Summary Background Data: Esophagectomy after nCRT is associated with tumor positive resection margins in 4% to 9% of patients. This study evaluates potential risk factors for positive resection margins after nCRT followed by esophagectomy. Methods: All patients who underwent an elective esophagectomy following nCRT in 2011 to 2017 in the Netherlands were included. A multivariable logistic regression was performed to assess the association between potential risk factors and tumor positive resection margins. Results: In total, 3900 patients were included. Tumor positive resection margins were observed in 150 (4%) patients. Risk factors for tumor positive resection margins included tumor length (in centimeters, OR: 1.1, 95% CI: 1.0–1.1), cT4-stage (OR: 3.0, 95% CI: 1.2–6.7), and an Ivor Lewis esophagectomy (OR: 1.6, 95% CI: 1.0–2.6). Predictors associated with a lower risk of tumor positive resection margins were squamous cell carcinoma (OR: 0.4, 95% CI: 0.2–0.7), distal tumors (OR: 0.5, 95% CI: 0.3–1.0), minimally invasive surgery (OR: 0.6, 95% CI: 0.4–0.9), and a hospital volume of >60 esophagectomies per year (OR: 0.6, 95% CI: 0.4–1.0). Conclusions: In this nationwide cohort study, tumor and surgical related factors (tumor length, histology, cT-stage, tumor location, surgical procedure, surgical approach, hospital volume) were identified as risk factors for tumor positive resection margins after nCRT for esophageal cancer. These results can be used to improve the radical resection rate by careful selection of patients and surgical approach and are a plea for centralization of esophageal cancer care.