Objective: We have proposed that direct passages created between pulmonary parenchyma and large airways (airway bypass) could take advantage of the extensive collateral ventilation present in emphysematous lungs to provide improvement in expiratory flow and respiratory mechanics. A critical step in the safe performance of these procedures is to create passages through the airway wall into lung parenchyma while avoiding injury to adjacent blood vessels. Methods: The procedure consists of selection of a target site bronchoscopically, use of a Doppler catheter to detect and avoid peribronchial blood vessels, and creation of a passage through the airway wall with a cautery probe. To evaluate the safety of airway bypass, 10 patients were treated during prpscheduled lobectomies for neoplasm. The procedure was done after thoracotomy and immediately before resection and was confined to airways in the lung identified for removal. Airway bypass was subsequently performed in 5 patients undergoing lung transplantation for emphysema just before lung excision to evaluate the procedure in emphysematous patients. Results: Twenty-nine passages (1-5 per subject) were created in the patients undergoing lobectomy. Eighteen passages were created 3-4 per subject) in the patients undergoing transplantation. There were 2 instances of mild bleeding in the patients undergoing lobectomy and no bleeding in the patients undergoing transplantation. Both instances were treated with suction and topical application of epinephrine and resolved without incident. Conclusion: The results of this study confirm that passages can be made safely through the airways of human subjects. These clinical results support further investigation of the efficacy of the airway bypass procedure in patients with emphysema.