Diet is another factor which should be taken into consideration in this connection. The recent work of Hunt(39) indicates that this may influence the resistance of animals to some poisons. Our experiments, however, fail to show any difference in the toxicity of the caffein in guinea pigs, whether fed oats, carrots, or both, for different results were obtained on the same diet, and there seemed to be little or no difference in the toxicity of caffein when the diet was different. Other explanations suggest themselves to account for the results obtained. Seasonal changes have been assigned by a number of investigators as a cause of variation in the resistance to drugs. According to Focke,(24) frogs are more susceptible to digitalis in the spring than in the summer, while Moschkowitsch(61) and Edmunds(21) reported the very opposite results. Schmiedeberg's(80) observations on strophantin in frogs were in harmony with those of Edmunds(21) and Moschkowitsch.(61) Similar results were reported with guinea pigs. Harrington's(34) experiments indicate that stimulation of the vagus is less effective from October to January than from February to April, when they are also much more susceptible to operative procedure. Hunt found that the resistance of guinea pigs to aceto nitril is about twice as great in the summer months as it is in January and February. Race might also be thought of as an important factor in this connection. Since the guinea pigs used at different seasons of the year were of several varieties, there is no reason to suppose, however, that the varieties experimented upon in the summer were more resistant than those used in the winter and spring. It is highly probable, therefore, that the greater resistance to caffein of the guinea pigs of series C than those of series B was due to seasonal variation. Doses of 0.20 to 0.24 gram caffein per kilo weight, therefore, may be regarded as the minimum fatal dose for the guinea pig, depending upon the season. Since 0.2 gram per kilo proved to be rapidly fatal in series B, this quantity was perhaps not the minimum fatal dose for the guinea pig at the season during which the experiments were made. Additional tests with smaller doses were therefore carried out during February and March. The results are shown in series D. SERIES D. _Guinea pig 49. Male. Weight, 510 grams. Diet, oats for 1 month previous to experiment._ March 17: 3 p. m., 4 cc 2 per cent caffein (0.16 gram per kilo) were injected subcutaneously; 4.40 p. m., reflexes increased; 5.40 p. m., no symptoms. March 18: 9 a. m., found dead, died in less than 18 hours. _Autopsy_: Hemorrhage into abdominal cavity; liver and spleen unduly congested; intestines injected; hemorrhagic area at point of injection. _Guinea pig 40. Male. Weight, 630 grams. Diet, oats and carrots one week previous to injection._ February 12: 11 a. m., 5 cc 2 per cent caffein (0.158 gram per kilo) injected subcutaneously into back.