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Percutaneous transluminal coronary angioplasty (PTCA) has greatly benefited patients with occluded coronary arteries, but its benefits have been undermined by a high incidence of restenosis. The introduction of coronary stents has significantly improved the short and long term outcome but restenosis still occurs in approximately 15-30 % of patients within 6 months. Research efforts are now being directed toward combination stenting and drug delivery. Among the therapeutic targets being pursued are agents which can impede smooth muscle cell (SMC) migration and proliferation as these processes are critical components of restenosis injury. We propose that inhibiting the conversion of ribonucleotides to deoxyribonucleotides will impede cell proliferation and as such limit the degree of restenosis. Therefore, we tested whether the potent Ribonucleotide Reductase (RR) inhibitors, Didox and Imidate, can limit the neointimal proliferation associated with restenosis using rat, rabbit and porcine models of vascular injury. Results demonstrated that systemic administration of the RR inhibitors Didox, Imidate and Hydroxyurea significantly reduced intimal thickening, intima/media ratio and lumen loss. Results from cell proliferation studies suggest that the mechanism of protection is inhibition of SMC proliferation and decreased number of circulating leukocytes. These results suggest that inhibition of Ribonucleotide Reductase may provide a potent strategy to prevent post PTCA restenosis.