Previous studies have shown that influenza A virus can activate the polymorphonuclear leukocyte (PMN) respiratory burst and that upon subsequent stimulation of the cell there is depressed metabolic function. We examined the mechanism by which influenza virus causes PMN dysfunction by measuring the effect upon the chemiluminescent activity of cells of varying the type of influenza virus used, the period of time that cells were exposed to virus, and the secondary stimulus that was used. The various types of intact influenza virus elicited different amounts of chemiluminescent activity, but when cells were subsequently stimulated with phorbol myristate acetate, each virus caused equivalent depression of the PMN response. Purified glycoproteins incorporated into a liposome structure similarly stimulated the PMN chemiluminescence, yet did not induce PMN dysfunction. Depressed PMN function was noted after as little as 5 min of incubation of cells with virus and occurred to both receptor-dependent (zymosan, N-formylmethionyl-leucyl-phenylalanine, and phorbol myristate acetate) and -independent (calcium ionophore A23187) stimuli.