We have shown previously that normal human neutrophils triggered by immune complexes displayed significant levels of cytotoxicity towards non-sensitized target cells (non-specific cytotoxicity-NSC) (Geffner, J. R. et al. 1987). Despite the fact that NSC and antibody-dependent cellular cytotoxicity (ADCC) are both mediated through neutrophil Fc gamma R and require the activation of the respiratory burst, the cytolytic mechanisms involved in each case appear to be different. In order to analyse the pathways of activation involved in the induction of NSC and ADCC, we studied here some of the metabolic requirements associated with each cytotoxic function. Our results suggest that ADCC is dependent on Na+/H+ antiporter activity, de novo protein synthesis, availability of external Ca2+ and calmodulin activity, activation of phospholipase C and activation of protein kinase C. On the other hand, NSC appears to be dependent on availability of external Ca2+ and calmodulin activity and activation of phospholipase A2. These results indicate that different pathways of activation are involved in the induction of neutrophil-mediated ADCC and NSC.