An experimental model of Listeria monocytogenes pneumonia was employed in order to study the pathogenesis of lung infection with a facultative intracellular pathogen in normal and steroid-treated hosts. Guinea pigs, which resemble humans as a "steroid-resistant" species, were treated with week-long regimens of cortisone acetate or saline. Cortisone regimens were 100 mg/kg/day (low-dose) or 200 mg/kg/day (high-dose). Lungs were then infected with Listeria monocytogenes, and groups were compared for survival as well as intrapulmonary killing of Listeria. A dose-dependent defect in pulmonary resistance to Listeria was observed among the steroid-treated animals, with survivals of 67% for the low-dose group and 0% for the high-dose group. Similarly, acquired in vivo pulmonary resistance to Listeria was diminished in steroid-treated animals, as reflected by reduced intrapulmonary killing and a tendency for systemic dissemination of Listeria. Numbers of T-lymphocytes in blood (p less than 0.001) and lungs (p less than 0.001) were significantly reduced in cortisone-treated animals. In addition, alveolar macrophages obtained from high-dose-treated animals displayed a 47% reduction in listericidal activity. It is concluded that glucocorticosteroid administration causes a dose-dependent reduction in pulmonary defenses to intracellular pathogens in the steroid-resistant host, and that suppression of both acquired local immunity as well as nonimmune defense mechanisms occurs.