Certain ACE inhibitors can decrease pulmonary and renal fibrosis resulting from exposure to ionizing radiation, possibly related to their intrinsic free radical scavenging properties. This study was designed to determine if ACE inhibitors can alter the pattern of lung injury and fibrosis induced by prolonged hyperoxia. Sixty male Sprague-Dawley rats were randomized into four groups: control (receiving neither oxygen nor drug), oxygen exposed controls(receiving no drug), oxygen exposed Captopril treated (a thiol containing ACE inhibitor), and oxygen exposed Enalapril treated (a non-thiol containing ACE inhibitor). Rats were exposed to 98-100% oxygen for 36 hours; 90% oxygen for 36 hours then maintained in 80% oxygen until their sacrifice on study day 5, 25, or 48. Captopril (400mg/L) and Enalapril (260mg/L) were provided continuously via drinking water. Samples of blood, lung and liver were examined for histologic and biochemical evidence of injury. Weight gain was decreased in all oxygen exposed animals regardless of drug treatment. Histologic evidence of acute oxygen toxicity (pulmonary edema) was present in all oxygen exposed animals regardless of therapy. Intensity of immunostaining for α-SMA (a marker of transformed myofibroblasts) seen around respiratory bronchioles, in alveolar walls and at septal tips was decreased with chronic ACE inhibitor treatment. Immunostaining of lipocytes and type II alveolar epithelial cells with PCNA (a marker of the S1 phase of cellular division) was prominent in all oxygen exposed animals on day five, but decreased at later time points. Intensity and distribution of immunostaining for PDGF and fibronectin was not altered by drug treatment. Immunostaining of liver and lung lipocytes and large airway epithelium with TGFβ decreased with chronic ACE inhibitor treatment. Staining for collagen deposition and elastic fibers around respiratory bronchioles, in alveolar walls and at septal tips was less prominent in ACE inhibitor treated animals at 45 days. We suggest that ACE inhibitors may decrease the long term effects of hyperoxia in rats through their effect on TGFβ production.