Neonatal rats were treated with low doses of bacterial ipopolysaccharide (endotoxin) to test for a protective effect of endotoxin against O2toxicity and the severe inhibition of normal lung development which occurs during prolonged exposure to hyperoxia. The rationale for the prophylactic use of endotoxin included its marked protective effect against pulmonary O2toxicity in adult rats and its lung growth-promoting effect in experimental pulmonary stress models. Neonatal rats (4-5 days old) survived a 14-day exposure to >95% O2equally well whether treated with saline (39/51=76%) or with endotoxin (41/51=80%). However, during the following 24 h of gradual weaning to room air breathing, there was a marked difference in survival between the endotoxin group (32/41=78%) and the saline pups (14/39=36%) (p<0.001). Both groups showed inhibition of lung development (alveolarization) during O2exposure, but endotoxin treatment compared to saline was associated with increased specific lung volume (5.33 versus 4.50 ml/100 g) (air control=4.08), smaller mean airspace diameter (mean linear intercept=49.0 versus 55.8 μm) (air control=43.3), increased specific internal surface area (4393 versus 3232 cm2/100 g) (air control=3753), and greater preservation of alveolar wall capillary patency (24.83 versus 18.52% “capillary density”) (air control=27.70%). We conclude that endotoxin treatment resulted in significant protection against O2toxicity in neonatal rats which was manifested during readaptation to room air breathing. The protective effect was likely due to a combination of reduced inhibition of lung growth and development and reduced hyperoxic damage to the respiratory membrane of the lung.