The effects of oral administration of various doses of indomethacin, ibuprofen, and flurbiprofen were studied in acute nonimmune pleurisy induced by calcium pyrophosphate crystals (CaPP) in the rat. Drug effects on pleurisy development, as measured by the pleural fluid volume, the number of emigrating leukocytes, and the in vitro oxygen uptake and hydrogen peroxide production of elicited polymorphonuclear neutrophils (PMNs) were investigated. Indomethacin (1.5, 3, and 6 mg/kg) induced a dose-dependent reduction of both exudate volume and number of emigrating leukocytes which reached approximately 50% of control values. A similar inhibition of these two inflammation parameters was observed for the three doses of ibuprofen (6, 18, and 54 mg/kg) and flurbiprofen (0.5, 1.5, and 4.5 mg/kg). The ability of elicited neutrophils to consume oxygen upon stimulation by serum-treated zymosan particles (STZ) was not altered in PMNs derived from animals treated with indomethacin or flurbiprofen, whereas a 35% decrease was induced by ibuprofen. Ibuprofen, but not indomethacin or flurbiprofen, also impaired STZ-induced PMN production of hydrogen peroxide. Furthermore, this inhibition was inversely related to ibuprofen doses. These data indicate that, in addition to their common properties to reduce leukocyte emigration at inflammatory sites, certain NSAIDs such as ibuprofen, but not flurbiprofen or indomethacin, impair particle-induced oxygen-dependent killing activities of elicited PMNs.