The physiological consequences of the deuterium isotope effect in large mammals were studied in two dogs, one of which was maintained at 20% concentration of D2O in the body fluids for 50 days, and the other at the toxic range of 33–35% for a brief period. Deuteration of the dogs was effected by replacement of ordinary water with deuterium oxide in both food and drink. Hemoglobin, hematocrit, and red blood cell count dropped but the white blood cell count was essentially unaffected although there was a progressive lymphopenia and granulocytosis. Serum glucose was decreased, especially at higher deuterium levels. Total serum cholesterol values were also diminished although the esters were essentially unchanged. Serum sodium and both NPN and BUN were within normal limits except for a terminal elevation of the latter. Serum potassium was slightly lowered for a brief period after 3 weeks. Electrocardiograms showed ST segment coving and elevation and an increase in the QT ratio that suggested nonspecific myocardial damage; these changes reverted to normal while the dog was still deuterated at a level of 20%. Both dogs exhibited neuromuscular disturbances, in one case definite weakness of the hind legs and in the other, fine muscle tremors.