The actions of 6 mM colchicine and 3.5 mM chloramphenicol on the phagocytic processes and oxidative metabolism of human neutrophils were examined. Heatkilled Staphylococcus aureus, heat-killed Candida albicans, and polystyrene microspheres were used to induce phagocytosis. The compounds affected three distinct aspects of the phagocytic process, and produced three effects: inhibition of particle uptake, dissociation of particle uptake from the overall oxidative-metabolic response of the neutrophil, and elimination of hexose-monophosphateshunt activation from the overall oxidative-metabolic response. In colchicinetreated neutrophils, the first effect predominated in studies with polystyrene, the second predominated in studies with S. aureus, and the third predominated in studies with C. albicans. In chloramphenicol-treated neutrophils, dissociation of particle uptake from the metabolic response predominated in studies with polystyrene, whereas elimination of the hexose-monophosphate shunt was dominant in the tests with S. aureus and C. albicans. Both drugs inhibited the hexosemonophosphate shunt but not the overall consumption of oxygen by nonphagocytic neutrophils stimulated by the dye, phenazine methosulfate. These data show that colchicine and chloramphenicol have multiple effects on neutrophil function and demonstrate that factors related to the ingested particle exert significant influences on the metabolic response of the neutrophil to phagocytosis.