A slightly elevated urinary albumin excretion rate (UAER), above 5-10 microgram/min, is a predictor of atherosclerotic cardiovascular disease. Endothelial dysfunction is an important early feature of atherosclerosis. The plasma concentration of von Willebrand factor (vWF), a potential marker of endothelial dysfunction, predicts a subsequent increase of UAER in patients with diabetes. The aim of this study is to test the hypothesis that high concentrations of vWF as well as other haemostatic factors predict progression of UAER in clinically healthy subjects. UAER was measured together with selected markers of haemostatic function-vWF, tissue plasminogen activator (tPA), plasminogen activator inhibitor, factor VII and fibrinogen-in healthy volunteers aged 40-65 years. After a mean follow-up of 4.1 years, 64 of 74 agreed to a re-examination including re-measurement of UAER. Baseline vWF and tPA were both positively correlated to the change in UAER during follow-up (r=0.26, P=0.04 and r=0.40, P=0.001 respectively). The mean UAER increased significantly by 7.6 microgram/min and 7.5 microgram/min respectively in subjects with vWF and tPA above the medians at baseline (P=0.01 and P=0.003 respectively), whereas no changes in UAER were seen in subjects with vWF and tPA below the medians. Subjects with high tPA were also characterized by an excess of other cardiovascular risk factors at baseline. No significant differences in these risk factors were present between subjects with high or low vWF. High plasma concentrations of vWF and tPA are associated with progression of UAER in clinically healthy subjects. Both vWF and tPA are secreted by endothelial cells and the results suggest that endothelial dysfunction leads to progression of UAER.