Background: The first and only randomized trial comparing open esophagectomy (OE) with minimally invasive esophagectomy (MIE) showed a significant lower incidence of post-operative respiratory infections in the patients who underwent MIE. In order to identify which specific factors are related to a better respiratory outcome in this trial an additional analysis was performed. Methods: This was a prospective, multicenter, randomized controlled trial. Eligible patients, with a resectable intrathoracic esophageal carcinoma, including the gastro-esophageal (GE) junction tumors and Eastern Cooperative Oncology Group ≤2, were randomized to either MIE or OE. Respiratory infection investigated was defined as a clinical manifestation of (broncho-) pneumonia confirmed by thorax X-ray and/ or Computed Tomography scan and a positive sputum culture. A logistic regression model was used. Results: From 2009 to 2011, 115 patients were randomized in 5 centers. Eight patients developed metastasis during neoadjuvant therapy or had an irresectable tumor and were therefore excluded from the analysis. Fifty-two OE patients were comparable to 55 MIE patients with regard to baseline characteristics. In-hospital mortality was not significantly different [2% (open group) and 4% (MIE group)]. A body mass index (BMI) ≥26 and OE were associated with a roughly threefold risk of developing a respiratory infection. Conclusions: Overweight patients and OE are independently associated with a significant higher incidence of post-operative respiratory infections, i.e., pneumonia.