To evaluate the influence of the elastase inhibitor, eglin-c, on lung host defense, normal CD-1 mice were challenged intratracheally with type 3 Streptococcus pneumoniae suspended in phosphate-buffered saline alone or containing 10 mg/ml eglin-c. After infection with 5 X 10(3) colony-forming units (cfu), animals given eglin-c demonstrated a significant enhancement in their capacity to clear viable pneumococci from the lungs at 24 h after challenge; the augmented pulmonary clearance was associated with an increased influx of granulocytes at 6 and 24 h. After challenge with higher inocula (5 X 10(4) and 5 X 10(5) cfu), animals treated with eglin-c exhibited a significant impairment in pulmonary clearance at 6 h; however, in the presence of larger numbers of granulocytes within the bronchoalveolar spaces, the attenuation in pulmonary clearance resolved between 6 and 24 h. Changes in the kinetics of pulmonary clearance that were similar to those noted after infection with high pneumococcal inocula were also observed after challenge with 1 X 10(6) cfu Staphylococcus aureus. In addition, although it did not influence the in vivo phagocytic capacity of resident alveolar against S. aureus, eglin-c depressed the bactericidal activity of these cells. We conclude that in the mouse, high doses of eglin-c alter pulmonary antimicrobial mechanisms important for preventing and eradicating bacterial infection of the lower respiratory tract.