Adherence to a Mediterranean diet (MD) is associated with a reduced risk of coronary heart disease. However, the molecular mechanisms involved are not fully understood. The aim of this study was to compare the effects of 2 MD with those of a low-fat-diet (LFD) on circulating inflammatory biomarkers related to atherogenesis. A total of 516 participants included in the Prevention with Mediterranean Diet Study were randomized into 3 intervention groups [MD supplemented with virgin olive oil (MD-VOO); MD supplemented with mixed nuts (MD-Nuts); and LFD]. At baseline and after 1 y, participants completed FFQ and adherence to MD questionnaires, and plasma concentrations of inflammatory markers including intercellular adhesion molecule-1(ICAM-1), IL-6, and 2 TNF receptors (TNFR60 and TNFR80) were measured by ELISA. At 1 y, the MD groups had lower plasma concentrations of IL-6, TNFR60, and TNFR80 (P < 0.05), whereas ICAM-1, TNFR60, and TNFR80 concentrations increased in the LFD group (P < 0.002). Due to between-group differences, participants in the 2 MD groups had lower plasma concentrations of ICAM-1, IL-6, TNFR60, and TNFR80 compared to those in the LFD group (P ≤ 0.028). When participants were categorized in tertiles of 1-y changes in the consumption of selected foods, those in the highest tertile of virgin olive oil (VOO) and vegetable consumption had a lower plasma TNFR60 concentration compared with those in tertile 1 (P < 0.02). Moreover, the only changes in consumption that were associated with 1-y changes in the geometric mean TNFR60 concentrations were those of VOO and vegetables (P = 0.01). This study suggests that a MD reduces TNFR concentrations in patients at high cardiovascular risk.