The toxicity of caffeine administered daily by intragastric cannula to female albino rats was determined over 100 days, i.e., 1/10 of the animal's life-span. The maximal LD 0(0.1L) or maximal daily dose producing no deaths over 100 days was 110 ± 2.5 mg/kg; the LD 50(0.1L) , 150 ± 3.1 mg/kg; and the minimal LD 100(0.1L) , 191 ± 5.7 mg/kg. Doses of the order of the LD 0(0.1L) produced a mild cerebral hyperemia, occasional psychotic-like self mutilation, gastric ulcers, and inhibition of oogenesis; hypertrophy of the salivary glands, gastrointestinal tract, liver, heart, kidneys, and lungs; a stressor reaction in the adrenal and thymus glands; minor changes in organ water levels; an occasional death apparently from bronchopneumonia; but in general a normal appearance, and no change in growth rate, eating and drinking habits, or in the volume, pH, and protein and glucose content of the urine. Doses of the order of the LD 50(0.1L) also produced a polydipsia and diuresis and an occasional dermatitis; some degree of toxic nephritis, hepatitis, myositis, thyroiditis, and loss of red pulp in the spleen. Doses of the order of the minimal LD 100(0.1L) and higher produced an increasingly more toxic reaction, which was similar to that seen in the syndrome at the acute oral LD 50 dose and that due to fortnight partial starvation. Abrupt withdrawal of caffeine was followed for 1 week by decreased locomotor activity, a slight decrease in colonic temperature, and proteinuria and glycosuria.