Elevated systemic hematocrit (Hct) increases cardiovascular risk, such as stroke and myocardial infarction. One possible pathophysiological mechanism could be a disturbance of the blood - endothelium interface. It has been shown that blood interacts with the endothelial surface via a gel-like layer ('glycocalyx', or 'endothelial surface layer - ESL') that modulates various biological processes, including inflammation, permeability, and atherosclerosis. However, consequences of an elevated Hct on the functional properties of this interface are incompletely understood. In a transgenic mouse (tg6) model exhibiting systemic Hct levels of about 0.85 the glycocalyx/ESL was nearly abolished. The corresponding increase in vessel diameter had only minor effects on peripheral flow resistance. This suggests that the pathological effects of elevated Hct may relate stronger to the biological corollaries of a reduced ESL thickness and alterations of the blood-endothelium interface, than to an increased flow resistance.