We investigated the importance of neurokinin-1 (NK-1) receptors in epithelial injury, repair and neutrophil function. Conscious Wistar rats were exposed to 1-ppm ozone or filtered air for 8 hours followed by an 8-hour post-exposure period. Prior to exposure we administered either the NK-1 receptor antagonist, SR 140333, or saline as a control. Ethidium homodimer was instilled into lungs as a marker of necrotic airway epithelial cells. After fixation, whole mounts of airway dissected lung lobes were immunostained for BrdU, a marker of epithelial proliferation. Both Ethidium homodimer and BrdU positive epithelial cells were quantified in specific airway generations. Rats treated with the NK-1 receptor antagonist had significantly reduced epithelial injury and epithelial proliferation compared to control rats. Sections of terminal bronchioles showed no significant difference in the number of neutrophils in airways between groups. Additionally, staining ozone exposed lung sections for active caspase 3 showed no apoptotic cells but ethidium positive cells co-localized with the orphan nuclear receptor, Nur77, a marker of non-apoptotic, programmed cell death mediated by the NK-1 receptor. An immortalized human airway epithelial cell line (HBE-1) showed no significant difference in the number of oxidant stress positive cells during exposure to H₂O₂ and a range of SR 140333 doses demonstrating no antioxidant effect of the receptor antagonist. We conclude that activation of the NK-1 receptor during acute ozone inhalation contributes to epithelial injury and subsequent epithelial proliferation, a critical component of repair, but does not influence neutrophil emigration into airways.