Objective: The objective is to determine the optimal manner to remove a chest tube after pulmonary resection. Method: This was a prospective, randomized single-institution study. Patients who underwent elective thoracotomy for pulmonary resection by 1 or 2 general thoracic surgeons were randomized to have their chest tube removed on either full inspiration or full expiration. Both patient groups performed a Valsalva maneuver during tube removal. Outcomes included the incidence of clinically nonsignificant pneumothorax (defined as a new or increased pneumothorax on the post-chest tube removal chest roentgenogram in asymptomatic patients), symptoms, delayed discharge, and the need for a new chest tube. Results: Between November 2008 and June 2011, 1189 patients underwent pulmonary resection, and of these 342 met the criteria for the study. Of the 179 patients randomized to have their chest tube removed on full inspiration, 58 (32%) had a larger or new pneumothorax after chest tube removal and 5 (3%) required intervention or delayed discharge. Of the 163 patients randomized to have their chest tube removed on full expiration, 32 (19%; P = .007) had a larger or new pneumothorax after chest tube removal, and only 2 (1%) required intervention or delayed discharge (P = .78). Conclusions: Removal of chest tubes at the end of expiration leads to a lower incidence of non-clinically significant pneumothorax than at the end of inspiration. Because of these findings, this study was closed early and was thus underpowered for finding a statistically significant difference in the rare (1%-3%) clinically significant pneumothoraces. © 2013 by The American Association for Thoracic Surgery.