Nonvalvular atrial fibrillation is associated with an overall risk of stroke of 4.5% per year. Advancing age, prior stroke or transcient cerebral ischemia, diabetes and hypertension are known risk factors. Ischemic stroke in patients with atrial fibrillation are generally more severe than ischemic stroke in patients with sinus rhythm. Warfarin is effective for primary and secondary prevention of ischemic stroke, reducing the risk by 68%. The effect of aspirin is still controversial, reducing the risk by 18-44%. Recent clinical trials have investigated the effect of warfarin given at a very low intensity either alone or combined with aspirin. The results from the SPAF III study demonstrated that a combination of mini-intensity warfarin plus aspirin was insufficient for stroke prevention in atrial fibrillation. Other trials now indicate, that oral anticoagulation at INR-values below 2.0 is not effective for stroke prevention in these patients. It is recommended that patients at high risk of stroke are treated with warfarin at an intensity of INR 2.0-3.0. Patients younger than 65 without other risk factors can be given aspirin 325 mg/day. The present clinical challenge is to ensure effective and safe oral anticoagulation to patients with atrial fibrillation at high risk of stroke.