Using a disease model, the current economic burden of stroke in the 2.3 million US patients with atrial fibrillation was estimated, and potential savings in direct costs obtainable by optimization of oral anticoagulation were projected using a disease model. Cost estimates were based on published epidemiologic data on risks in 3 main prevention scenarios (ie, none or aspirin alone, warfarin in routine care, and warfarin in anticoagulation clinic settings) and 2003 Medicare cost data. According to the model described, the approximately 1.265 million (55%) patients currently not receiving prophylaxis, suffer 58 382 strokes annually with an associated total direct cost to Medicare of dollar 4.8 billion. For the 1.035 million receiving warfarin, 38 468 strokes are predicted every year, costing an estimated dollar 3.1 billion. If 50% of those not receiving warfarin prophylaxis were optimally anticoagulated, 19 380 emboli would be prevented and dollar 1.1 billion would be saved. If 50% of those currently receiving warfarin in routine medical care were optimally anticoagulated, 9852 emboli would be prevented and dollar 1.3 billion would be saved. The risk of bleeding increases in the first of these "what if" scenarios but drops substantially in the second. These estimates do not account for the costs of optimization. Given the continued underutilization and poor anticoagulation control observed with warfarin, despite 50 years of use and widespread awareness of its effectiveness, the feasibility of achieving the projected 50% increases in optimal usage is questionable. Although efforts to optimize warfarin use must continue, the best opportunity for Medicare or managed care organizations to reduce stroke rates and costs at magnitudes approaching those analyzed in this model may come with use of newer oral anticoagulants that are easier to manage.