Endoluminal vacuum therapy (EVT) is an accepted treatment for anastomotic leakage (AL) after esophagectomy. A novel concept is to use this technology in a preemptive setting, with the aim to reduce the AL rate and postoperative morbidity. Preemptive EVT (pEVT) was performed intraoperatively in 19 consecutive patients undergoing minimally invasive esophagectomy, immediately after completion of esophagogastrostomy. Twelve patients (63%) were high-risk cases with severe comorbidity. The EVT device was removed routinely three to six (median 5) days after esophagectomy. The endpoints of this study were AL rate and postoperative morbidity. There were 20 anastomoses at risk in 19 patients. One patient (5.3%) experienced major morbidity (Clavien-Dindo grade IIIb) unrelated to anastomotic healing. He underwent open reanastomosis at postoperative day 12 with pEVT for redundancy of the gastric tube and failure of transition to oral diet. Mortality after 30 days was 0% and anastomotic healing was uneventful in 19/20 anastomoses (95%). One minor contained AL healed after a second course of EVT. Except early proximal dislodgement in one patient, there were no adverse events attributable to pEVT. The median comprehensive complication index 30 days after surgery was 20.9 (IQR 0-26.2). PEVT appears to be a safe procedure that may have the potential to improve surgical outcome in patients undergoing esophagectomy.