Upon activation, basophilic granulocytes release inflammatory mediators, such as histamine. We studied histamine release (HR) of purified (64 +/- 10%) human basophils after cross-linking of membrane-bound IgE via anti-IgE or after binding of the chemoattractant formyl-methionyl-leucyl-phenylalanine (FMLP). A variability in the extent of histamine release upon stimulation by either anti-IgE or FMLP was found between donors. Non-responders for FMLP showed high histamine release for anti-IgE, and vice versa. Inhibition of protein kinase C (PKC) by staurosporine (STSP) resulted in partial inhibition of the anti-IgE-induced HR, whereas inhibition of a PKC-independent pathway by wortmannin (WTM) totally blocked the anti-IgE induced histamine release. The HR induced by FMLP was not affected by either of these inhibitors. We conclude that major differences exist in the signal-response coupling between the anti-IgE and FMLP-induced HR in human basophils. The so-called releasability of human basophils may be due to the availability of different cell activation pathways.