An attempt has been made to determine a maximum safe digitalizing dose of digoxin for healthy premature infants. The experimental design has utilized a three-by-three Latin square, in which premature infants in three predetermined weight and age categories have been assigned at ran dom to each of three digitalizing dosages: 30, 50 and 75 µ/kg body weight of digoxin. The total scheduled dosage was administered intramuscularly in three equally divided doses at 8-hour intervals. Control electrocardiograms were taken, and tracings were obtained after two-thirds of the dosage had been given, 4 hours after digitalization was completed, and at 24-hour intervals thereafter. Digitalis intoxication was defined in terms of electrocardiographic criteria. Twenty-seven infants were tested with 30 µg/kg body weight of digoxin, 26 with 50 µg/kg and 27 with 75 µg/kg. The incidence of digitalis intoxication was 2.5% at the 30 µg/kg dosage level, 9.4% at 50 µg/ kg, and 33.3% at 75 µg/kg. The null hypothesis is rejected with a high degree of probability. Insufficient data were available for statistical analysis of age differences in incidence of intoxication. The data indicates, however, that premature infants tested during the first 72 hours of life may have a diminished tolerance to the glycoside. Side-effects of glycoside administration were noted in only a few of the infants, were rarely severe and were short-lived. The electrocardiographic manifestations of digitalis intoxication were widely varied. Sinus node depression with ectopic supra-ventricular beats and rhythms, and atrio-ventricular conduction disturbances were the most common arrhythmias observed. An irritable ventricular focus was observed in only 1 of the 12 intoxicated infants. In most cases a regular sinus rhythm had returned with 48 hours of full digitalization. However one infant still had evidence of arrhythmia 9 days later. On the basis of the data presented, the following conclusions are reached: 1. The administration of 75 µg/kg body weight of digoxin, for the digitalization of healthy premature infants, in the manner described, incurs an excessive risk of digitalis intoxication. 2. Although 50 µg/kg represents a more reasonable risk among these infants, and 30 µg/kg a minimal risk, one must be alert to the occasional infant who may have an unusual intolerance to the drug. It is recommended that digitalization be carried out under close electrocardiographic control, as no clinical criteria correlated well with the development of digitalis intoxication in these infants. Tracing of adequate length, in which the P waves are well defined, should be obtained during digitalization and at daily intervals until the infant is being given a stable maintenance dosage.