To evaluate the effect of maturation on the renal disposition of digoxin, the ratio of digoxin clearance to creatinine clearance was determined in 35 patients who were 3 days to 79 yr old. All were at steady-state levels for digoxin treatment. A mean ratio of 1.49 ± 0.67 (SD) was obtained in the group of prepubertal children and infants ≥2 mo of age. The mean ratio decreased to 0.82 ± 0.25 (SD) in the adult group; adults were defined as sexually mature adolescents or older (P < 0.005). The decrease in net renal tubular secretion of digoxin appears to occur at puberty. This observation can provide one explanation for the apparently larger doses of digoxin required by infants and children than by adults. It may also represent a developmental change in renal tubular physiology with broader significance than for digoxin disposition alone.