Abstract: Killing of bacteria by neutrophils is dependent upon the availability of potassium. Although macrophages derived from human peripheral blood monocytes have little killing activity of their own, they can be transformed into effective killers of Staphylococcus aureus and Mycobacterium tuberculosis by in vitro exposure of the macrophage to clinically relevant concentrations of phenohiazines, namely, thioridazine or chlorpromazine. Because transport mechanisms dependent upon the availability of calcium are inhibited by these agents, the possibility that other agents which have similar activity also have the ability to enhance the killing of bacteria by the macrophage derived from peripheral blood monocytes was investigated. In this study we show that the presence of increasing concentrations of ouabain, reserpine or verapamil in the medium enhances the killing of Staphylococcus aureus. Because these concentrations have no activity on the replication or killing of the bacterium, killing is deemed to be due to the macrophage itself. A model is presented which describes the mechanism by which these agents and phenothiazines indirectly activate lysosomal enzymes as a result of the inhibition of potassium efflux pumps that would normally pump the ion from the phagocytic vacuole to the cytoplasm of the macrophage.