Background: Seven randomized trials have demonstrated that anticoagulant therapy is effective for primary and secondary prevention of stroke and other thromboembolic events in patients with chronic nonvalvular atrial fibrillation. The effect of aspirin is still not clarified. Conventional anticoagulant therapy is inconvenient as a primary preventive therapy as it requires frequent blood tests and implies a risk of bleeding complications. Purpose and methods: The Second Copenhagen Atrial Fibrillation, Aspirin and Anticoagulant Therapy Study (The AFASAK 2 study) is a randomized, one center, primary prevention trial. Its purpose is to investigate the effect of four antithrombotic regimens in patients with atrial fibrillation (1) fixed dose warfarin 1.25 mg per day, (2) a combination of warfarin 1.25 mg per day and aspirin 300 mg per day, (3) aspirin 300 mg per day, and (4) conventional warfarin therapy (INR 2.0-3.0). The primary endpoint is a stroke or a thromboembolic event in viscera or extremities. Secondary endpoints are transient ischemic attack, myocardial infarction, or death. The study will evaluate outcome events on intention-to-treat principles. The rate of bleeding complications is evaluated. The aim is to obtain an antithrombotic therapy for patients with nonvalvular atrial fibrillation that is effective, safe, easy to administer, and inexpensive. The methods and design of the study are presented in this paper.