We wish to propose a novel hypothesis of how exercise may beneficially modulate endothelial function. The benefit of exercise in the prevention of cardiovascular disease is undisputed, but the underlying mechanisms responsible for this beneficial effect, which are independent of traditional cardiovascular risk factors, remain poorly understood. Recently, attention has been focused on the influence of exercise on the endothelium, its functions, and its interactions with blood components. 1,2 Exercise training enhances NO and suppresses endothelin-1 production by the endothelium, 3 thus potentially shifting the balance toward vasodilation and antiatherosclerosis. Improved endothelium-dependent vasodilation (EDV) in both the coronary and peripheral vessels following exercise training has been demonstrated by a number of studies in human subjects of different age and risk groups. 4,5 In hypercholesterolemic patients, this improvement is independent of fasting lipid profile modification. 6 In cell culture experiments, shear stress induces an upregulation of endothelial NO synthase with resultant increase in NO production and release. With exercise training of small muscle groups, such as a handgrip exercise, the local increase in blood flow directly enhances EDV through shear stress mechanisms. 7 However, dynamic exercises that use larger muscle groups, such as bicycle ergometer training, produce a systemic enhancement of EDV. 4,8 In this setting, the systemic increase in shear stress is small, and it has been suggested that the systemic enhancement of EDV may be the result of metabolic or neurohormonal factors, which are modified by exercise. 9 However, to date no likely candidates have been identified.It has long been known that exercise training lowers postprandial lipemia: 10 an environment which is considered to be proatherogenic. 11 There is accumulating evidence that postprandial lipemia exerts its deleterious effect on the cardiovascular system by causing endothelial dysfunction. 12 There are now several studies demonstrating that postprandial lipemia induced by eating a fatty meal causes significant impairment of EDV in healthy humans and that the degree of impairment correlates with the rise in postprandial plasma triglyceride levels. [13][14][15] We believe it is plausible that postprandial plasma lipid levels (and/or their composition) represent the missing systemic factor that links exercise training with the general improvement in endothelial function observed in vivo. Thus, in daily life, regular exercise suppresses postprandial lipemia, and through this, endothelial function is enhanced. This intriguing hypothesis links for the first time the effects of exercise on postprandial lipemia and endothelial function, which until now have been investigated separately. To provide support for this hypothesis, novel study protocols that investigate the effects of exercise training and fat-meal challenge in combination on the outcome measure of EDV are required. Furthermore, because a reduction in postpran...