In response to mounting pressures to improve stroke prophylaxis for patients with atrial fibrillation, many hospitals and healthcare systems have opened specialty anticoagulation clinics. OBJECTIVE: The purpose of this study was to determine the cost-effectiveness of stroke prophylaxis from a hospital system perspective. METHODS: We have developed a decision model representing several options for stroke prophylaxis. Simulated patients could receive warfarin through either an anticoagulation clinic or their family physician, aspirin, or no therapy. Possible events were thromboembolic stroke, hemorrhagic stroke, hemorrhage requiring hospitalization (major hemorrhage), or hemorrhage requiring a clinic visit and/or warfarin dose adjustment (minor hemorrhage). Three different scenarios of stroke prophylaxis are presented: a health care system with an anticoagulation clinic (I); a system which maximizes anticoagulation with warfarin via the family physician (II); and a system which maximizes anticoagulation but utilizes anticoagulation clinics to a larger extent (III). RESULTS: Option I was the least costly and effective strategy with a 10 year average cost of $6327 / patient treated and a life expectancy of 7.728 years. The values for II and III were $6549 and 7.735 life years, and $6443 and 7.761 life years, respectively. The incremental cost-effectiveness was $34,339/ life-year saved for II versus I and $4013/ life-year saved for option III versus I. Option III was dominant over II. These results were sensitive to the cost per clinic or office visit and the rate of occurrence of major hemorrhage. CONCLUSION: Increasing warfarin utilization is cost-effective from a health-care system’s perspective. Anticoagulation clinics appear to be the best method for achieving this goal.