Platelet-mediated thrombus formation at the site of vascular injury is a major trigger for thrombo-ischemic complications after coronary interventions. The platelet collagen receptor glycoprotein VI (GPVI) plays a critical role in the initiation of arterial thrombus formation. Endothelial denudation of the right carotid artery in rabbits was induced through balloon injury. Subsequently, local delivery of soluble, dimeric fusion protein of GPVI (GPVI-Fc) (n = 7) or control Fc (n = 7) at the site of vascular injury was performed with a modified double-balloon drug-delivery catheter. Thrombus area within the injured carotid artery was quantified using a computer-assisted image analysis and was used as index of thrombus formation. The extent of thrombus formation was significantly reduced in GPVI-Fc- compared with control Fc-treated carotid arteries (relative thrombus area, GPVI-Fc vs. Fc: 9.3 +/- 4.2 vs. 2.3 +/- 1.7, p < 0.001). Local delivery of soluble GPVI resulted in reduced thrombus formation after catheter-induced vascular injury. These data suggest a selective pharmacological modulation of GPVI-collagen interactions to be important for controlling onset and progression of pathological arterial thrombosis, predominantly or even exclusively at sites of injured carotid arteries in the absence of systemic platelet therapy.