In 100 patients receiving digoxin to control heart disease, metabolic reduction of the lactone ring of digoxin was investigated. An average of 12.4% +/- 11% (range 2.2% to 52%) of the lipid-extractable cardenolides in a 24-hour urine sample contained the reduced lactone ring. Fifty-three excreted more than 10% while seven excreted more than 35% of these metabolic products. Reduction was not influenced by age, sex, dose, or blood level of digoxin. One patient who excreted 52% reduced products in the urine had 40% reduced digoxin-metabolites in the blood; the main metabolite was dihydrodigoxin. We found no influence of other drug therapy or concurrent disease on reduction of digoxin in this group.