To evaluate the basis for the hemorrhagic diathesis associated with oral anticoagulant therapy plus the hypolipidemic agent clofibrate, this interaction was studied in 8 normal subjects. Administration of clofibrate 2.0 g/day alone for 14 days had no effect on the platelet count, bleeding time, platelet aggregation, plasma adenosine diphosphatase, platelet release of adenosine diphosphate and adenosine triphosphate, platelet-collagen adhesion, one-stage prothrombin time, or vitamin K-dependent clotting factors (II, VII, IX and X) but significantly reduced platelet adhesiveness and epinephrine-induced platelet aggregation. After addition of large single doses of sodium warfarin, 1.5 mg/kg body weight, to the clofibrate regimen, all values remained within the normal range, including platelet adhesiveness, except epinephrine-induced platelet aggregation. The one-stage prothrombin activity and clotting factors II and X were significantly lower with warfarin plus clofibrate than with warfarin alone, but the plasma level of warfarin was unchanged. Co-administration of sodium warfarin and clofibrate for 21 days augmented the hypoprothrombinemia observed in long-term therapy with warfarin alone but caused no significant change in the plasma warfarin level. It is concluded that the hemorrhagic complications of therapy with warfarin plus clofibrate result primarily from the more rapid decline in the activities of clotting factors II and X and perhaps also from the reduced platelet aggregation.