Background: The regulatory function of the endothelium is altered in hypercholesterolemia, and the subsequent endothelial dysfunction plays a central role in the development of atherosclerosis. Objective: To determine whether endothelial function in hypercholesterolemic patients is affected by replacing a saturated fat-enriched diet with a low-fat, low-saturated fat diet (the U,S, National Cholesterol Education Program stage 1 [NCEP-1] diet) or a diet rich in monounsaturated fat (such as that common in Mediterranean countries). Design: Intervention dietary study with a baseline phase and two randomized crossover dietary periods. Setting: Hospital Universitario Reina Sofia, Cordoba, Spain, Patients: 22 hypercholesterolemic men. Intervention: Patients followed a diet high in saturated fat, then were assigned in a crossover design to the NCEP-1 diet or a Mediterranean diet. Each dietary period lasted 28 days. Measurements: Plasma P-seledin levels, lipid concentrations, and endothelial function, Results: Compared with the saturated fat diet, flow-mediated dilatation increased during the Mediterranean diet but not during the NCEP-1 diet In addition, levels of plasma cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, and P-selectin decreased during the NCEP-1 and Mediterranean diets. Conclusion: In hypercholesterolemic men, diets low in fat (especially saturated fat) and diets rich in monounsaturated fats improve endothelial function.