OBJECTIVES: We studied the effect of the Mediterranean diet on plasma levels of C-reactive protein (CRP), white blood cell counts, interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, amyloid A, fibrinogen, and homocysteine. BACKGROUND: To the best of our knowledge, the mechanism(s) by which the Mediterranean diet reduces cardiovascular risk are not well understood. METHODS: During the 2001 to 2002 period, we randomly enrolled 1,514 men (18 to 87 years old) and 1,528 women (18 to 89 years old) from the Attica area of Greece (of these, 5% of men and 3% of women were excluded because of a history of cardiovascular disease). Among several factors, adherence to the Mediterranean diet was assessed by a diet score that incorporated the inherent characteristics of this diet. Higher values of the score meant closer adherence to the Mediterranean diet. RESULTS: Participants who were in the highest tertile of the diet score had, on average, 20% lower CRP levels (p = 0.015), 17% lower IL-6 levels (p = 0.025), 15% lower homocysteine levels (p = 0.031), 14% lower white blood cell counts (p = 0.001), and 6% lower fibrinogen levels (p = 0.025), as compared with those in the lowest tertile. The findings remained significant even after various adjustments were made. Borderline associations were found regarding TNF-alpha (p = 0.076), amyloid A levels (p = 0.19), and diet score. CONCLUSIONS: Adherence to the traditional Mediterranean diet was associated with a reduction in the concentrations of inflammation and coagulation markers. This may partly explain the beneficial actions of this diet on the cardiovascular system.