Gene therapy remains a promising strategy for the treatment of human respiratory diseases such as Cystic Fibrosis, however with the improved efficacy of agents now tested, new questions arise about optimal formulation and administration. We have previously shown uptake and expression in the respiratory epithelium of rhesus monkeys treated by aerosol with liposomes complexed with CFTR cDNA. With further improvements in liposome formulation, we reevaluated safety and efficacy of a liposome formulation for delivery of CFTR or other reporters to the lower airway. Animals were sedated and allowed to breath spontaneously the DNA-liposome complex using a unique low pressure closed aerosol system. No immediate adverse effects were evident, and no animals exhibited any signs of respiratory distress. Three days after treatment the lungs were evaluated for immunohistochemical evidence of CFTR overexpression, evidence of reporter gene activity, or transgene RNA by RT-PCR. Depending on the specific material adminestered, the efficacy of this method was clearly demonstrated, and no adverse effects were noted. We conclude that liposomes are an effective method of transferring exogenous genes to the lower respiratory tract when administered by aerosol. *KEY*Cystic fibrosis, Gene therapy, Liposome gene delivery