A potent antiparasitic effect against a broad range of microorganisms is now known to follow the administration of cyclosporine A (CSA) to a variety of mammalian species and birds. Even though in the case of Schistosoma mansoni a direct antischistosomal effect by CSA has been in principle ruled out, this possible mechanism of action has not been previously explored in depth. In this paper we show that (a) concentrations of CSA of as low as 1 microgram/ml are schistosomulicidal in vitro as determined by morphological criteria, (b) mice receiving antischistosomal regimens in vivo exhibit serum concentrations of CSA that are within the range of toxic doses in vitro, (c) schistosomulicidal concentrations of CSA are maintained in vivo for sufficiently long periods of time to secure parasite death, (d) the antischistosomal activity of heat-inactivated mouse sera closely correlates with their levels of CSA, and (e) independent of the site of administration, CSA offers protection against a schistosomal infection in vivo only when present in the serum. The data strongly support the contention that CSA has a direct effect on the early forms of Schistosoma mansoni, and suggest that interference with a survival mechanism, perhaps common to several parasites, represents one likely mode of action.