The metabolic pattern of cardioactive and conjugated digitoxin metabolites was studied in 10 uremic patients on maintenance treatment with digitoxin 24 hr after the last dose (mean dose, 0.060 mg/day). Urine was collected over 24 hr. The mean serum digitoxin level was 9.4 ng/ml, and urine level was 6.8 ng/ml. The metabolic pattern of cardioactive metabolites was studied in 5 patients on hemodialysis. Their mean serum digitoxin level was 6.3 ng/ml and urine level was 7.3 ng/ml, on a digitoxin dose of 0.072 mg/day. Unchanged digitoxin was the main cardioactive substance present in both serum and urine of uremic patients. Uremic patients had significantly less unchanged digitoxin and had more hydroxylated (DG-3) and hydroxylated and hydrolyzed (DG-2, DG-1, and DG-0) metabolites than control patients. The extent of conjugation was the same in the two groups. Our data suggest that uremic patients produce more digitoxose than control patients and that digitoxin elimination is more rapid in uremic patients. The altered pattern of digitoxin metabolites is most consistent with uremia-induced changes in hydroxylation and hydrolysis. The hemodialysis group had a pattern of digitoxin and cardioactive metabolites similar to control patients, indicating that patients on hemodialysis differ from other uremic patients with respect to digitoxin metabolism.