In a large number of experiments on caffein performed in this laboratory it has been observed that symptoms due to caffein often disappeared when the administration of the same dose of the drug was continued. Thus dog 19 vomited when the amount of caffein was increased to 125 mg per kilo. When this amount was repeated the next day there was no vomiting. Similar observations were made on dogs 11 and 23, also on other dogs. No. 22 developed diarrhea at first; when the administration of caffein was resumed several days later, however, there was no diarrhea. In other experiments performed in this laboratory, symptoms of nervous irritability induced by caffein disappeared on continued treatment. It was interesting, therefore, to inquire whether resistance to caffein would be increased by the continued administration of progressively larger amounts of the drug. When doses of 150 and over were fed, the intervals allowed were usually longer than 24 hours. Two and sometimes three days were permitted to elapse between two successive doses. This was done in order to allow time for recovery from possible changes induced by larger doses of caffein, and thus prevent the summation of effect. In the experiments considered, therefore, Nos. 11, 23, 20, and 19, the toxicity of caffein does not seem to be greater than in the experiments on acute caffein intoxication in the dog. It was thought, however, that the large initial doses or the quick change to large doses when the amounts used in the beginning were small, might have something to do with failure to induce a marked degree of tolerance. The experiment on dog 21 was therefore carried out by giving from 40 to 60 mg per kilo for eight days, and then increasing the dose, but tolerance could not be induced, as is shown in the protocol to the experiment. SERIES B. According to the studies of Chittenden,(16) low protein diet improves the general metabolism of the body, fatigue is diminished, and bodily vigor, therefore, correspondingly increased. The expectation is, therefore, justified that the defense of the organism against deleterious substances introduced into the body is much improved by such a diet, thus increasing its resistance to poisons. Hunt's experiment on this subject, also quoted by Chittenden, lends support to this view. He found that mice fed on carbohydrates chiefly, or on foods containing only a small amount of protein, were more resistant to acetonitril. It was interesting, therefore, to inquire whether the toxicity of caffein differs under similar conditions of diet.