With the purpose of examining the significance of macrophage neutral proteases for the random migration of guinea pig peritoneal macrophages, we tested the influence of the polyvalent protease inhibitor, Trasylol (100-2000 KIU/ml), and the serine protease inhibitor, phenylmethyl sulphonyl fluoride (PMSF; 10(-4)-10(-3) M), on this function. Using the capillary method, the migration of resident and oil-induced cells was examined under different culture conditions: absence of serum; presence of 10% of either intact (IHS) or acid-treated horse serum (AHS). Protease inhibitors only reduced the locomotion of inflammatory macrophages. Trasylol caused a dose-dependent reversible macrophage migration inhibition the degree of which depended upon the conditions in culture (AHS greater than no HS greater than IHS). The irreversible effects of PMSF were better in the presence of serum. Although the migration of control macrophages occurred at the three different quantitative levels (AHS greater than IHS greater than no HS), there were no differences in the migration kinetics under the action of these antiproteases compared to the corresponding control, which, together with the preserved cell viability indicates that the drugs did not act deleteriously on macrophages. Our results suggest that macrophage neutral proteases do not only play an important role in delayed hypersensitivity, as previously demonstrated, but also in the random migration of inflammatory macrophages. Furthermore, it is shown that the clinical application of Trasylol may have an influence on this vitally important macrophage function.