Inhaled GM-CSF shows promise as a therapeutic to treat viral and bacterial pneumonia, but to date, no mouse model of inhaled GM-CSF has been described. We sought to: 1) develop a mouse model of the administration of aerosolized recombinant mouse GM-CSF; and 2) investigate the protection conferred by inhaled GM-CSF during influenza A virus (IAV) infection against secondary bacterial infection with pneumococcus. To assess lower respiratory tract delivery of aerosolized therapeutics mice were exposed to aerosolized fluorescein-labeled dextran non-invasively via an aerosolization tower, or invasively using a rodent ventilator. The efficiency of delivery to the lower respiratory tracts of mice was 0.01% non-invasively as compared to 0.3% invasively. The airway pharmacokinetics of inhaled GM-CSF fit a two compartment model with a terminal phase half-life of 1.3 h. To test if lower respiratory tract levels were sufficient for biological effect, mice were infected intranasally with IAV, treated with aerosolized recombinant mouse GM-CSF, then secondarily infected infected with . Inhaled GM-CSF conferred a significant survival benefit to mice against secondary challenge with (p<0.05). Inhaled GM-CSF did not reduce airway or lung parenchymal bacterial growth, but significantly reduced the incidence of bacteremia (p<0.01). However, GM-CSF overexpression during influenza virus infection did not affect lung epithelial permeability to FITC-dextran ingress into the bloodstream. Therefore, the mechanism of protection conferred by inhaled GM-CSF appears to be locally-mediated improved lung antibacterial resistance to systemic bacteremia during IAV infection.