Six subjects receiving digoxin therapy for heart disease were studied on two occasions with a single oral dose of 0.5 mg of tritiated digoxin. In every study, all stools and urine were saved for 1 week. Before the second study, treatment with cholestyramine, 4 g every 6 hours, was begun and continued throughout. In three patients, a third study was performed after cholestyramine treatment had been continued for 1 month. Results showed that after cholestyramine administration serum levels, stool output and urinary output of tritiated digoxin varied over a wider range, but cholestyramine had no net short-term effect of any of these variables. After 1 month of cholestyramine administration, there was a small statistically significant increase in stool output of tritiated digoxin and metabolites. In vitro studies suggested that cholestyramine is likely to be a weak digoxin binder in the gut and that changes induced by this resin in digoxin metabolism are not likely to be due to drug binding.