Normal human neutrophils, incubated with 0.2 mg/ml opsonized zymosan particles, were found to lyze human (H), ox (O) and chicken (C) red blood cell (RBC) targets as determined by the 51Cr release assay. The susceptibility to the lysis of the different target cells was HRBC < ORBC < CRBC. An intact neutrophil metabolic burst was essential for the cytotoxic event, since neutrophils from a patient with chronic granulomatous disease failed to kill all three target cells. HRBC and ORBC destruction was prevented by catalase and unaffected by azide, suggesting the requirement of hydrogen peroxide alone in the lethal hit. CRBC destruction was abolished by catalase and azide, suggesting the involvement of the myeloperoxidase-hydrogen peroxide system. Thus, different neutrophil cytolytic systems may become operative and may vary in their efficiency depending on the type of target cells.