<jats:p> <jats:italic>Background</jats:italic> —Enoxaparin inhibits smooth muscle cell proliferation in experimental models. Intimal hyperplasia has been found to be the principal cause of restenosis after coronary stent implantation. We sought to determine whether the intramural delivery of enoxaparin before stenting of de novo lesions decreases restenosis. </jats:p> <jats:p> <jats:italic>Methods and Results</jats:italic> —One hundred patients who were undergoing stenting were randomly assigned to either local administration of enoxaparin during predilation with reduced systemic heparinization or stenting with standard, systemic heparinization. All patients were treated with the same type of stent (NIR). The primary study end point was late luminal loss. The secondary end points were major adverse cardiac events, target lesion revascularization, and angiographic restenosis at 6 months. Angiographic follow-up at 6 months was completed in all except 1 patient. Late luminal loss was reduced to 0.76±0.42 mm in the local enoxaparin delivery group versus 1.07±0.49 mm in the systemic heparinization group ( <jats:italic>P</jats:italic> <0.001). Restenosis, using a binary definition, occurred in 10% of patients in the enoxaparin group and in 24% of patients in the systemic heparinization group ( <jats:italic>P</jats:italic> <0.05). Target lesion revascularization rates occurred in 8% of the enoxaparin group and 22% of the systemic heparinization group ( <jats:italic>P</jats:italic> <0.05). There were no deaths and no emergent CABGs were performed. The only subacute stent closure and non–Q-wave infarction occurred in a patient assigned to the systemic heparinization group. </jats:p> <jats:p> <jats:italic>Conclusions</jats:italic> —This is the first prospective randomized trial in which the local delivery of a drug, enoxaparin, resulted in significant reduction in late luminal loss and restenosis after stent implantation in de novo coronary lesions. </jats:p>