An attempt was made to study the effect of furosemide on the toxic and lethal dose (LD) of ouabain. Ouabain was infused continuously in guinea pigs anesthetized with urethane. The toxic dose of ouabain was determined by the minimal dose which produced ventricular arrhythmias. The LD of ouabain was 300.8 +/- 13.8 microgram/kg (mean +/- SE) in control guinea pigs. When furosemide was administered in a dose of 2 mg/kg i.v. prior to ouabain, this was significantly decreased to 225.2 +/- 14.1 microgram/kg (P less than 0.01). Furosemide-treated guinea pigs also showed a marked decrease in toxic dose of ouabain. In another series of experiment, the ouabain uptake by the heart and its subcellular fraction were determined by the infusion of 3H-ouabain at a constant rate under the same experimental conditions aforementioned. Approximately 30% decrease in the LD of 3H-ouabain was also observed in the furosemide pretreated guinea pigs. 3H-ouabain concentration in blood, cardiac muscles and microsomal fraction were lower than control group. These findings suggest that potentiation of ouabain toxicity produced by furosemide is not associated with increased cardiac ouabain uptake, but with increased sensitivity at the site of action.