Our aim was to evaluate the effectiveness of oral anticoagulation (OAC) in patients aged ≥80 years with nonvalvular atrial fibrillation in daily clinical practice. From February 1, 2000 to June 30, 2009, we enrolled all patients aged ≥80 years with nonvalvular atrial fibrillation attended at 2 outpatient cardiology clinics of a tertiary care university hospital. The patients received antithrombotic treatment according to the recommendations from scientific societies and were prospectively followed, with major events (i.e., all-cause death, stroke, transient ischemic attack, peripheral embolism, severe bleeding) analyzed according to the treatment group (OAC vs no OAC). Of 269 patients included in the present study (87 men, mean age 83 ± 3 years), 164 received OAC (61%). After 2.8 ± 1.9 years of follow-up, the raw rates (per 100 patient-years) of embolic events (1.52% vs 8.30%, p <0.0001) and mortality (6.67% vs 10.94%, p = 0.04) were lower for patients receiving OAC, with a nonsignificant greater rate of severe bleeding (3.03% vs 1.25%, p = 0.14). The probability of survival free of major embolic or hemorrhagic events at the mean follow-up was greater for patients receiving OAC (82.27% vs 66.10%, p = 0.004). After adjustment for age, gender, coronary heart disease, and embolic risk, evaluated using the CHADS(2) score (congestive heart failure, 1 point; hypertension [blood pressure consistently >140/90 mm Hg or hypertension medication], 1 point; age ≥75 years, 1 point; diabetes mellitus, 1 point; previous stroke or transient ischemic attack, 2 points), only OAC was an independent predictor of embolic events (hazard ratio 0.17, 95% confidence interval 0.07 to 0.41, p <0.001). The CHADS(2) score (hazard ratio 1.32, 95% confidence interval 1.01 to 1.73, p = 0.04) and OAC (hazard ratio 0.52, 95% confidence interval 0.31 to 0.88, p = 0.01) were independent predictors of mortality. In conclusion, OAC according to the scientific societies' recommendations is effective and safe in daily clinical practice, even in patients aged ≥80 years.