Vascular smooth muscle cell (VSMC) growth is a primary component of accelerated and spontaneous atherosclerosis. Previous studies have shown that iron may be involved in the control of enzymatic activities that modulate DNA synthesis in human cells. In this study the effects of the iron chelator desferrioxamine on in vitro and in vivo VSMC proliferation were tested. Rat VSMCs in culture and a rabbit model of carotid artery balloon injury were used. Desferrioxamine showed a significant inhibitory effect on [3H]thymidine incorporation in cell cultures that was antagonized by iron supplementation. Desferrioxamine also provided effective preventive myointimal VSMC proliferation as assessed by bromodeoxyuridine labeling and morphometric analysis of endoluminal stenosis. These experiments suggested that iron may be involved in the control of VSMC proliferation and that desferrioxamine may have a role in preventing VSMC growth and myointimal proliferative lesions.