Objective: To evaluate the feasibility of catheter-based endobronchial electroporation for the treatment of peribronchial tumors and assess the incidence of treatment-related adverse events. Methods: Cytotoxicity of electroporation with or without cisplatin or gefitinib was assessed in vitro with lung cancer and normal cell lines. A novel catheter was designed for endobronchial electroporation, and computer simulations were used to predict in vivo treatment effects. Electroporation with the test catheter was performed (2000 V, 70 pulses) in the main bronchus of 8 pigs at 11 locations. Computed tomography imaging was performed before they were killed at 4 hours (6 animals) or 4 weeks (2 animals) posttreatment. Treated airway and surrounding parenchyma were compared with sham treatment via gross and histopathology. Results: Significant cell death due to electroporation and increased cytotoxicity in combination with cisplatin or gefitinib were observed in cancer cells only (P <.05). Simulations predicted penetrative electroporation of peribronchial parenchyma without tissue heating. Electric pulse delivery in vivo induced transient venous and bronchial spasms that resolved without intervention. Cross-sectional measurement of electroporation effects on computed tomography (14.4 ± 1.4 by 10.5 ± 1.3 mm) and gross pathology (17.2 ± 3.0 by 8.8 ± 0.6 mm) were representative of values predicted by simulation (P <.001). Cell death due to irreversible electroporation was observed in bronchial and parenchymal tissue in acute tissue samples. Treated lung rapidly recovered from the effects of electroporation without change in bronchial patency at 4 weeks posttreatment. Conclusions: Catheter-based endobronchial electroporation is a reproducible technique that can be used to treat peribronchial tumors in combination with cisplatin, without affecting patency of the treated bronchus.