Recent evidence suggests complement (C) -stimulated granulocytes (PMNs) are important in a variety of diseases, including shock and myocardial infarction (MI). Corticosteroids inhibit PMN response to C and show promise in some studies of shock and MI, but their use has not become routine for several reasons. Synergy was sought among agents inhibiting PMN aggregation in vitro in response to activated C: methylprednisolone (MP), with a 50% inhibitory dose (AD50) of 0.6 mg/ml; ibuprofen (IBU), with AD50 of 1.0 mg/ml, and betahistine (BH), with AD50 of 1.6 mg/ml. Simultaneous use of all three agents produced 3.4-fold synergy; 3-fold synergy obtained between IBU + MP and IBU + BH, while 1.5-fold synergy was noted between MP + BH. Further, MP and IBU were at least additive in inhibiting · O2-a generation by FMLP-stimulated PMNs and in blocking directed migration. In a preliminary in vivo test of this finding, cats were given MP and IBU-in known individually ineffective doses-immediately prior to coronary artery ligation. Neither MP nor the low dose of IBU chosen limited the size of the resultant MI, while both agents together reduced MI size by 42%. Synergy among these agents suggests that they inhibit PMN function of distinct cellular mechanisms (as yet not elucidated). Further, early in vivo results encourage speculation that such synergy might ultimately be exploited clinically, although such speculation must presently be regarded as preliminary.