In order to determine how cortisone might be used with the greatest practical value as a therapeutic agent for patients with a chronic illness such as rheumatoid arthritis, clinical studies were undertaken to observe the result of relatively small doses with definite anti-rheumatic effect given over a period of one year or more. As judged by clinical findings, some patients with rheumatoid arthritis tolerated well the prolonged use of cortisone, while others did not. Laboratory tests to determine the responsiveness of the human adrenal gland to stimulation by carticotropin, shortly after discontinuance of prolonged cortisone treatment, showed a satisfactory physiological response in the majority of the patients. In parallel with these observations, animal studies were conducted to determine whether daily injections of cortisone acetate for a period of time comparable to one year in man would produce irreversible structural changes in the rat adrenal gland.Method of Study Material.-Albino rats of the Sherman strain, 3 months old, were used. All animals were obtained from the dealer at the same time. The female rats weighed 190 to 240 g., and the males 190 to 260 g. All rats were housed under the same conditions and were given water and a complete Rockland stock diet ad libitum, with the exception that in one series food was restricted to provide undernourished control animals. The cortisone acetate used in these studies was the usual suspension (25 mg./ml.) injected intramuscularly into arthritic patients. The diluent employed for control was the vehicle used by the manufacturer for suspending the cortisone acetate, a saline solution containing suspending agents and 1 *5 per cent. benzyl alcohol.Experimental Animals.-Intramuscular injections of cortisone acetate were given to 25 male and 25 female rats. On the first day they received 9 mg. cortisone acetate in 0 6 ml. of the suspending vehicle, and on each of the succeeding 10 days each rat received 3 mg. steroid in 0-2 ml. vehicle. The total amount of cortisone acetate given during this 1 1-day injection period was 39 mg. to each rat. The daily dose of 3 mg. was calculated to be ten times the equivalent of a human daily dose of 100 mg., based on comparative average body weights. Control animals were also injected for 11 days, subsequently referred to as "the injection period".The cortisone-treated rats were divided into five groups of ten animals each, with five males and five females in each group. Each, group was killed at different intervals after the last injection: 1, 3 5, 7, 14, and 30 days.Controls.-A group of 66 rats, 33 male and 33 female, used as controls, was divided into three series: Series I, 4 males and 4 females, untreated, served as controls for growth and development over the 41-day period of observation (11 days of injection and 30 days of recovery).Series II, 16 females and 16 males, were injected intramuscularly with the diluent only. These animals received 0 6 ml. diluent on the first day and 0 2 ml. daily on each of the succeeding 10 days...