The effect of treatment with the nonsteroidal anti-inflammatory agent piroxicam on leukocyte migration to the lungs was investigated after aerosol administration of sublethal doses of Pseudomonas aeruginosa to mice. Piroxicam decreased, in a dose-related fashion, the polymorphonuclear leukocyte recruitment to, and the degree of perivascular and peribronchial infiltration in, the lungs. Piroxicam treatment also protected the animals in a dose-dependent manner from challenge with lethal doses of P. aeruginosa. The effect of piroxicam was not related to direct action of the drug on the microorganisms. Piroxicam treatment maintained the animal's pulmonary defenses against infection while diminishing inflammatory responses against P. aeruginosa, an occurrence decreasing the potential for tissue damage due to phagocytes migrating from circulation.