Recent studies suggest a role of endothelin-1 (ET-1) in mediating airway inflammation and lung injury. The aim of this study was to assess the immunohistochemical expression of ET-1 in the lung following smoke inhalation injury. ET-1 immunoreactivity was assessed in normal sheep (N = 4) and in sheep at 1 (N = 2), 6 (N = 3), 12 (N = 3), and 24 (N = 3) hours after inhalation injury. In normal animals, ET-1 expression was limited to the basal cell layer of the tracheal epithelium, main bronchi, and associated mucous glands. One hour after injury, ET-1 immunoreactivity was enhanced in upper airway epithelium and mucus glands with new expression in bronchioles. Airway smooth muscle, vascular tissue, and alveolar duct smooth muscle cells expressed moderate levels of ET-1 at 12 and 24 hours. ET-1 immunoreactivity was absent in areas of parenchymal edema and inflammation. The pattern of ET-1 expression following inhalation injury suggests that this peptide may contribute to the airway inflammation, mucus secretion, pulmonary hypertension, increased airway resistance, and decreased lung compliance, which are evident in our ovine model of inhalation injury.