The in vivo and in vitro effects of cyclosporin A on T. cruzi were examined. Mice receiving 150 or 75 mg/kg/day of cyclosporin A and infected with T. cruzi 48 hr later had significantly higher parasitemias and earlier mortality than controls. Mice receiving cyclosporin A after infection had parasitemias similar to controls. Infections with both the reticulotropic Y and the miotropic CL strains of T. cruzi were enhanced by cyclosporin A. The in vitro replication of epimastigotes, but not the intracellular replication of amastigotes, in mouse macrophages was inhibited by 5 µg cyclosporin A/ml. Enhancement of the infection by cyclosporin A was not due to an effect of macrophages since the drug did not prevent development of activated macrophages capable of killing intracellular T. cruzi.