Morphine is known to increase the turnover of neuronal histamine and release histamine from mast cells. The contribution of histamine H-1 and H2 receptors to some of the morphine effects on the central nervous system are also known. The role of mast cell histamine content in the hypothermic effect of morphine and the thermoregulatory effect of compound 48/80 was investigated in the present experiments. In order to observe its thermoregulatory effect, various doses of compound 48/80 is administered to the 1^st group. In the 2^nd group, compound 48/80 is injected chronically (1^st day-0.5 mg/kg, 2^nd day-1 mg/kg, 3^rd day-2 mg/kg, 4^th day-3 mg/kg, 5^th day-4 mg/kg) to deplete mast cell contents. Morphine injection (10 mg/kg), although it produced significant hypothermic effect when administered alone, did not exert its hypothermic effect after chronic compound 48/80 treatment. Our results indicate that the hypothermic effect of morphine in mice is mediated by histamine, liberated from mast cells.