Administration of a therapeutic dose level of digoxin in the intact dog resulted in an augmentation of the glucose utilization of the myocardium accompanied by a greatly increased rate of glycolytic and oxidative activity. The contribution of glucose to the total metabolism of the heart was increased, and the utilization of noncarbohydrate substrates was decreased. These metabolic changes occurred in the absence of changes in the dynamic functions of the heart, indicating that the metabolic alterations were due to a primary effect of the drug rather than an effect secondary to an altered state of cardiac activity.