Atrial fibrillation (AF) is characterized by enhanced oxidative stress and is complicated by cardiovascular events (CVEs), which are only partially prevented by anticoagulant treatment. The Mediterranean diet (Med-Diet) has a positive effect on atherosclerotic progression. In a prospective cohort of 709 anticoagulated AF patients, adherence to Med-Diet was assessed to investigate whether Med-Diet may reduce CVEs by lowering oxidative stress. The cohort was divided into three groups according to the Med-Diet score: low (0-3 points), medium (4-6 points), and high (7-9 points) adherence. During a mean follow-up of 39.9 months (2604.8 patients/year), we registered 72 (2.8%/year) CVEs: 23.4% in the low-adherence group, 8.4% in the intermediate-adherence group, and 5.3% in the high-adherence group (p<0.001). There were no differences in time in the therapeutic range among groups. The Med-Diet score was inversely correlated with sNOX2-dp (soluble NOX2-derived peptide; Rs: -0.297, p<0.001) and F2-isoprostanes (F2-IsoP; Rs: -0.411, p<0.001). Median values of sNOX2-dp (p<0.001) and F2-IsoP progressively decreased across groups (p<0.001). A Cox regression analysis showed that the Med-Diet score (HR: 0.771, p=0.001), F2-IsoP (HR: 1.002, p=0.004), and heart failure (HR: 1.876, p=0.024) predicted CVEs. In conclusion, these findings raise the hypothesis that adherence to Med-Diet could be associated with a reduction of CVEs, through an antioxidant effect, as shown by a concomitant downregulation of Nox2 and decreased excretion of F2-IsoP.