We have studied the effects of digoxin administration on Na+/K(+)-ATPase activity in heart, liver, muscle, renal medulla and aorta in the rat. Adult male rats were either treated with digoxin for 3 days, 7 days (5 mg/kg per day) or 3 months (3 mg/kg per day). Another group of rats were treated with the vehicle as controls. At the end of the experimental period, blood samples were taken for digoxin measurements, the animals were sacrificed, and the heart, liver, kidney, skeletal muscle and aorta were removed, homogenised and assayed for Na+/K(+)-ATPase activity. In all tissues except the aorta Na+/K(+)-ATPase activity was measured by an enzyme coupled reaction. Na+/K(+)-ATPase activity in the aorta was measured by a fluorometric potassium dependent 3-O-methyl fluorescein phosphatase activity. Plasma digoxin concentration in the digoxin group was 5.34 nmol/l (S.E.M., 0.09) in the 3-day group and 4.38 (0.68) and 4.89 (0.73) nmol/l in the 7-day and 3-month groups, respectively. After treatment for 3 days and 7 days, the Na+/K(+)-ATPase activity in all tissues was significantly lower in the digoxin group (the decrease in activity ranging from 13.4% in muscle to 46.9% in the renal medulla). After 3 months of treatment, Na+/K(+)-ATPase activity in all the tissues except the aorta was similar in the digoxin and control groups. In the aorta the activity remained low. We conclude that in rats digoxin administration causes upregulation of the Na+/K(+)-ATPase in most tissues.