Chronic venous insufficiency (CVI) is inseparably linked to elevated venous pressure and is accompanied by vascular, dermal, and subcutaneous tissue damage and restructuring. Abundant evidence exists both in humans and in experimental models to suggest that the tissue damage may be initiated by generation of an inflammatory reaction. Inflammatory indicators include elevation of endothelial permeability; attachment of circulating leukocytes to the endothelium; infiltration of monocytes, lymphocytes, and mast cells into the connective tissue; and development of fibrotic tissue infiltrates and several molecular markers, such as growth factor or membrane adhesion molecule generation. Indicators of an inflammatory reaction are already detectable at early stages of CVI and may be involved in the development of primary venous valve dysfunction. One of the important questions is to identify trigger mechanisms for the inflammatory reaction in CVI. Current evidence suggests that, among several possible mechanisms (hypoxia, humoral stimulation), a shift in fluid shear stress from normal physiological levels and endothelial distension under the influence of elevated venous pressure may serve as trigger mechanisms for inflammation.