Objective: Recent experimental evidence suggests that the neointimal proliferation seen in cardiac allograft vasculopathy may in part derive from recipient progenitor cells. The effect of cyclosporine on these circulating progenitors in the setting of cardiac transplantation is currently unknown. Methods: Three surgical series were performed: sham operation alone, sham operation with immunosuppression, and heterotopic porcine cardiac transplantation with immunosuppression. The sham operation involved laparotomy and consecutive clamping of the abdominal aorta and inferior vena cava. Post-operative immunosuppression consisted of cyclosporine at therapeutic levels (100-300 ng/ml) and 0.5 mg/kg methylprednisolone. Endothelial outgrowth colony numbers (EOC CFU) and smooth muscle outgrowth colony numbers (SOC CFU) were quantified weekly for 4 weeks post-operatively. A series of in vitro experiments were performed to determine the effect of cyclosporine on the differentiation, migration, and proliferation of EOCs and SOCs. Results: In the sham alone series there were no changes to either EOC CFU or SOC CFU. In the sham with immunosuppression and the transplant series, both EOC CFU and SOC CFU fell in the first 2 weeks (p < 0.05) compared with baseline (EOC CFU, 3.4 ± 0.6; SOC CFU, 11.1 ± 2.8). EOC CFU recovered at 4 weeks to above baseline levels in the sham immunosuppression group only (15.2 ± 3.9; p = 0.01). SOC CFU showed no recovery in the immunosuppression groups. Cyclosporine, even at a low dose, prevented differentiation, inhibited proliferation, and attenuated migration of both EOCs and SOCs. Conclusion: Immunosuppression in the setting of cardiac transplantation causes a profound reduction in circulating progenitor cells capable of differentiating into endothelial and smooth muscle cells. This effect can in part be explained by the inhibitory effects of cyclosporine on progenitor growth and differentiation seen in this study. Copyright © 2005 by the International Society for Heart and Lung Transplantation.