Respiratory syncytial virus (RSV) is a major respiratory pathogen in infants, young children and the elderly and causes severe bronchiolitis and asthma. In an effort to develop a preventive IFN-γ therapy against RSV infection, an intranasal gene transfer strategy was utilized. Intranasal administration of a plasmid expressing the IFN-γ cDNA (pIFN-γ) resulted in the expression of IFN-γ in murine lungs and decreased RSV replication. The mice administered with pIFN-γ and then infected with RSV exhibited a significant decrease in broncho-alveolar lavage lymphocyte and neutrophil counts. A significant reduction in epithelial cell damage, infiltration of mononuclear cells in the peribronchiolar and perivascular regions, and thickening of the septa was observed in the lungs of mice treated with pIFN-γ when compared to controls. These results suggest that intranasal IFN-γ gene transfer results in decreased RSV replication and pulmonary inflammation and may be useful against RSV infection.