The chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP), per se incapable of triggering cytotoxicity, was found to significantly enhance phorbol myristate acetate (PMA)-dependent monocyte-mediated cytolysis of human red blood cell (HRBC) targets. Target cell lysis by PMA triggered monocytes was related to the release of superoxide anion and hydrogen peroxide, since cells from patients with chronic granulomatous disease and cells from normal donors, in the presence of superoxide dismutase or catalase, failed to exert significant cytotoxicity. An increased release of these mediators was found to be responsible for the FMLP-dependent amplification of the cytolytic reaction. The results indicate that chemotactic factors are able to enhance the release of cytotoxic mediators by monocytes and raise the possibility that cellular processes during monocyte chemotaxis could modulate the subsequent cytolytic activity.