OBJECTIVE:We aimed to elucidate whether minimally invasive esophagectomy (MIE) can be safely performed by reviewing the Japanese National Clinical Database. SUMMARY OF BACKGROUND DATA:MIE is being increasingly adopted, even for advanced esophageal cancer that requires various preoperative treatments. However, the superiority of MIEʼs short-term outcomes compared with those of open esophagectomy (OE) has not been definitively established in general clinical practice. METHODS:This study included 24,233 esophagectomies for esophageal cancer conducted between 2012 and 2016. Esophagectomy for clinical T4 and M1 stages, urgent esophagectomy, 2-stage esophagectomy, and R2 resection were excluded. The effects of preoperative treatment and surgery on short-term outcomes were analyzed using generalized estimating equations logistic regression analysis. RESULTS:MIE was superior or equivalent to OE in terms of the incidence of most postoperative morbidities and surgery-related mortality, regardless of the type of preoperative treatment. Notably, MIE performed with no preoperative treatment was associated with significantly less incidence of any pulmonary morbidities, prolonged ventilation ≥48 hours, unplanned intubation, surgical site infection, and sepsis. However, reoperation within 30 days in patients with no preoperative treatment was frequently observed after MIE. The total surgery-related mortality rates of MIE and OE were 1.7% and 2.4%, respectively (P < 0.001). Increasing age, low preoperative activities of daily living, American Society of Anesthesiologists physical status ≥3, diabetes mellitus requiring insulin use, chronic obstructive pulmonary disease, congestive heart failure, creatinine ≥1.2 mg/dL, and lower hospital case volume were identified as independent risk factors for surgery-related mortality. CONCLUSIONS:The results suggest that MIE can replace OE in various situations from the perspective of short-term outcome.