Intrathoracic procedures can be performed with thoracoscopy in esophagectomy because the laparoscopic technique has recently been developed. During intrathoracic procedures, prone positioning of the patient allows gravity to facilitate optimal exposure of the esophagus, thereby affording a superb surgical view. In the current study, we compared the influence of prone positioning with lateral decubitus positioning on oxygenation in esophagectomy. We enrolled 18 patients and divided them into two groups: patients who underwent esophagectomy via thoracoscopy in the prone position (group P) and patients who underwent thoracotomy in the lateral decubitus position (control group, group L). Arterial blood gas analyses were performed before the operation was started (T1), 20 min after the initiation of one-lung ventilation (OLV) (T2), and two other points. The P/F ratio at T2 in group P was higher. Further, percent (%) change of the P/F ratios from T1 and thereafter in group P was higher at all points. We thought the reason why the prone position had contributed to maintenance oxygenation was as follows. First, the functional residual capacity and ventilation/perfusion matching in the prone position are satisfactory. Second, a bronchial blocker might contribute to reduction of atelectasis. Third, minimally invasive esophagectomy might reduce respiratory complications and blood loss because this procedure reduces edema and inflammation in the lung. In conclusion, the oxygenation provided by prone positioning is better than that provided by the lateral decubitus position during OLV in esophagectomy.