Several nonsteroid anti-inflammatory agents were evaluated for their capacity to modulate phagocytosis by and lysosomal enzyme secretion from polymorphonuclear neutrophils. During cell contact with and phagocytosis of serum-treated zymosan particles, guinea-pig neutrophils demonstrated a selective extracellular release of lysosome granule-associated beta-glucuronidase and acid protease but not cytoplasmic lactate dehydrogenase. Ketoprofen, suprofen, diftalone, benoxaprofen and Abbott 29590 inhibited particle uptake by and lysosomal enzyme release from neutrophils incubated with zymosan in Krebs-Ringer phosphate medium containing 7.5 mM glucose, pH 7.4, AT 37 degrees C. Flazalone and sulindac were inactive. In the presence of cytochalasin B, an agent which inhibits phagocytosis while having no effect on the selective discharge of lysosomal enzymes, ketoprofen, suprofen, diftalone, benoxaprofen and Abbott 29590 continued to inhibit the release of beta-glucuronidase and acid protease from neutrophils. An investigation of the properties of guinea-pig neutrophil acid protease activity revealed a pH optimum of 3.5. Activity was inhibited by diazoacetyl-DL-norleucine methyl ester and p-hydroxyphenylpyruvic acid. Sulfhydryl inhibitors, chelating agents and soybean trypsin inhibitor had no effect on neutrophil acid protease activity. These studies indicate that certain nonsteroid anti-inflammatory agents may function as regulators of the phagocytic secretion of lysosomal enzymes from neutrophils; and that these neutrophils contain an acid protease which resembles an enzyme known to mediate tissue destruction in several inflammatory diseases.