The purpose of this study was to evaluate the roles of matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator (uPA) with regard to varicose veins (VVs). Immunohistochemical staining and ELISA were performed on samples from 73 patients with the following leg VVs: 82 greater saphenous veins (GSV) from the groin (GSV groin), 28 GSV from the ankle (GSV ankle), 85 VVs, and 13 normal GSV groin (control [CR]) obtained during coronary artery bypass surgery. Immunohistochemically, MMP-9 was localized in the smooth muscle cells (SMCs) in the tunica media. The ratio of immunopositive cells of MMP-9 in the GSV groin, VVs, and GSV ankle were significantly higher than that of CR. The ratios of immunopositive cells of uPA and uPA receptor (uPAR) were not significantly different among the groups. uPA and uPAR were found to be positive in a different set of SMCs of the MMP-9-positive cells. An ELISA showed that the amount of uPA in the culture of the GSV groin was significantly higher than that in CR. For the remodeling process, MMP-9 may be produced in the VV wall and degrade elastic lamellae and other extracellular components of the venous wall. uPA may be produced by groin tissue of the GSV and flow downward because of valvular incompetence, activating MMP-9 at VV tissues.