Abstract: Atherosclerosis is a chronic inflammatory disease in which the fibrinolytic system has been implicated as playing a major role. In order to directly assess the physiological impact an imbalanced fibrinolytic system has on both early and late stages of this disease, mice deficient for PAI-1 (PAI-1−/−) were used in a model of vascular injury/repair and compared to wildtype mice (WT). Copper-containing cuffs were placed around the carotid arteries of these mice and the injured arteries were removed at either 7 or 21 days for histological analyses. At both times after injury, fibrin was prevalent in WT arteries, whereas only diffuse in PAI-1−/− arteries. At 21 days after injury, a prominent, multilayered neointima was evident in WT arteries, with no evidence of a neointima in PAI-1−/− arteries. Results from this study directly confirm the involvement of the fibrinolytic system in vascular repair processes following injury and indicate that fibrin could potentially play a role in lesion formation by stimulating smooth muscle cell proliferation, collagen synthesis, and intracellular cholesterol accumulation.