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BACKGROUND AND OBJECTIVE: Several studies comparing different intensities of oral anticoagulant treatment have clearly shown a relationship between bleeding complications and prolongation of prothrombin time. In the early '50s, de Takats suggested that low-dose oral anticoagulants might be as effective as higher doses in preventing thrombosis, at a lower risk of bleeding. This review article examines the potential of low dose warfarin therapy. INFORMATION SOURCES: The authors have been working in this field, contributing original papers. In addition, the material examined in this article includes articles published in the journals covered by the Science Citation Index and MedLine. STATE OF ART AND PERSPECTIVES: The hypothesis that low-dose oral anticoagulants can be effective in preventing thrombosis was first proven by experiments in animal models, and showed that a prothrombin time ratio as low as 1.14 using rabbit brain thromboplastin was still able to confer some inhibition of experimental thrombosis. Low-dose or very low-dose warfarin were subsequently demonstrated to be effective in patients with morbid obesity and decreased antithrombin III functional and antigenic levels, in patients with indwelling catheters, in patients undergoing gynecological surgery, as well as in patients with stage IV breast cancer. Low-dose warfarin is also effective in the prevention of embolic strokes in patients with non-rheumatic atrial fibrillation. However, older patients (> 75 years), who have a very high risk of bleeding, might be safer taking a very low dose of warfarin (i.e., a daily dose of 1-1.25 mg). Moreover, after a period of run-in, a fixed, very low-dose warfarin schedule does not need further laboratory control, which is a factor that could contribute to the full acceptance of treatment by patients and could stimulate a broader prescription of warfarin for the primary prevention of stroke in older patients with nonrheumatic atrial fibrillation. Therefore, we have organized a multicenter clinical trial in which 1000 patients with non-rheumatic atrial fibrillation will be randomized to receive either a fixed mini-dose of warfarin or a standard dose. Positive results might permit the treatment of most older patients with non-rheumatic atrial fibrillation, creating a benefit for the community as a consequence of its effective prevention of disabling strokes.