Immunosuppressants are necessary to prevent graft rejection after solid organ transplantation. However, they are also known to have significant side effects, including endothelial toxicity. Endothelial progenitor cells originate in the bone marrow and are recognized by their angiogenic and endothelial reparative properties. The effects of the immunosuppressants cyclosporine A (CyA), tacrolimus and rapamycin were analyzed on peripheral blood mononuclear cells under conditions which support growth of endothelial progenitor cells, as well as related cell types. The effect of rapamycin was profound upon endothelial progenitor cells. A much lesser effect was observed in mature human aortic endothelial cells, macrophages or late-outgrowth endothelial progentor-like cells. CyA and tacrolimus had no significant effects at clinical concentrations. The mechanism of cell death appeared to be apoptosis induced by a diverse mechanism. In conclusion, rapamycin induces endothelial progenitor cell death, probably related to the blockage of the necessary stimulatory drive on these cells given by growth factors.