Recent findings suggest that patients with non-valvular atrial fibrillation (AF), in addition to having a high risk for ischemic stroke, are also at risk for myocardial infarction (MI). The aim of the study was to combine factors predicting Major Adverse Cardiovascular Events (MACE) in AF patients, including fatal/nonfatal MI, cardiac revascularization, and cardiovascular death, into a simple risk score. Predictors of MACE were obtained from a prospective observational cohort study, including 1019 AF patients taking vitamin K antagonists from the Atherothrombosis Center, of Sapienza University of Rome. Thus, we derived the 2MACE score [2 points for Metabolic Syndrome and Age ≥75, 1 point for MI/revascularization, Congestive heart failure (ejection fraction ≤40 %), thrombo-Embolism (stroke/transient ischemic attack)], ranging from 0 to 7 points. To evaluate the 2MACE score, we included an external validation cohort of 1089 anticoagulated AF patients from the Thrombosis Centre of Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy. At follow-up, 111 AF patients in the internal and 68 in the external cohort experienced a MACE. The 2MACE score showed a good ability in discriminating AF patients experiencing MACE both in the internal derivation cohort, with a c-index of 0.79 [95 % Confidence Interval (CI) 0.71-0.90, p < 0.001] and in the external validation cohort (c-index 0.66, 95 % CI 0.60-0.73, p < 0.001). The overall Hazard Ratio (HR) was 1.61 (95 % CI 1.40-1.85, p < 0.001) for each additional point. A 2MACE score ≥3 had the best combination of specificity and sensitivity, with an HR of 3.92 (95 % CI 2.41-6.40, p < 0.001). The new simple 2MACE score may help identifying AF patients at risk for cardiovascular events.