Spironolactone has been reported to diminish the hypoprothrombinemic effect of oral anticoagulants in animals and digitoxin blood levels in man by induction of hepatic enzymes. To evaluate this in man, single oral doses of racemic warfarin, 1.5 mg/kg body weight, with and without 200 mg oral spironolactine daily, were administered to 9 normal subjects. Daily venous blood samples were analyzed for 1-stage prothrombin activity, hematocrit, and warfarin content. There was a decrease in hypoprothrombinemic effect (p less than 0.01), an increase in venous hematocrit (p less than 0.001), and no change in warfarin level (p greater than 0.5) during warfarin with spironolactone-induced diuresis over that with warfarin alone. It is concluded that the interaction of warfarin and spironolactone results primarily from the diuresis with consequent concentration of clotting factors and decreased anticoagulant effect.