The possibility that caffeine, a central nervous system stimulant used in neonatal apnea, may produce acute or chronic changes in growth hormone (GH), thyroxine (T4) and thyrotropin (TSH) was studied in the newborn rat. Five-day-old rats were separated into three groups: control (0) group receiving saline, Group I (low dose caffeine) receiving 5 mg/kg and Group II (high dose caffeine) receiving 50 mg/kg. Acute effects were studied at 2, 4, and 24 h after injection. Chronic effects were studied 24 h after the last of 10 daily injections. GH, T4, and TSH were measured by radioimmunoassay and caffeine by high pressure liquid chromatograph. GH was increased at all times and all doses after a single injection of caffeine. After chronic therapy, the increase in GH was small, suggesting depletion of pituitary reserve. A high dose of caffeine had a biphasic effect on T4 with an increase at 4 h and a decrease at 24 h. Thyrotropin-releasing hormone (TRH)-induced TSH release at 24 h was not influenced by caffeine administration. Chronic caffeine therapy stimulated both T4 and TSH; however, TRH-stimulated TSH release was decreased, suggesting that chronic therapy may blunt pituitary TSH response.