There are no published reports of successful percutaneous in vivo gene delivery to the pulmonary vascular bed without the use of adjunctive agents. The purpose of our study was to demonstrate the feasibility of recombinant reporter gene transfer to the pulmonary artery of pigs using naked plasmid DNA delivered via percutaneous catheter techniques involving angioplasty. Varying quantities of naked plasmid DNA containing the E. coli lacZ gene in a eukaryotic expression vector were used to transfect pigs that were 10kg to 20kg in weight. One technique for delivery of reporter gene to the pulmonary artery involved pressing plasmid DNA into the vessel wall during angioplasty using a standard angioplasty balloon which was coated with a solution of DNA mixed with heparin. The other delivery technique involved infusing DNA between an angioplasty balloon and a second, surrounding, perforated balloon. We allowed three days for gene expression and then harvested the pulmonary arteries. RNA from the pulmonary arteries was reverse transcribed, and cDNA was amplified by polymerase chain reaction using primers specific for lacZ. Foreign protein expression was evaluated with immunohistochemistry using a polyclonal antibody to β-galactosidase. Successful transcription and translation were determined for both delivery techniques in the treated but not contralateral pulmonary arteries. We conclude that pulmonary artery gene transfer using naked plasmid DNA delivered via percutaneous angioplasty techniques is feasible. The use of naked plasmid DNA removes the potential for toxicity associated with an adjunctive agent such as liposome or adenovirus. Additionally, ours is the first report of gene delivery to the pulmonary vascular bed using angioplasty. The development of this technique provides a novel method for the study of pulmonary vascular biology in vivo and establishes the feasibility of gene insertion into the pulmonary arteries.