The hypothermic response following intraperitoneal doses (6.25, 12.5, and 25 mg/kg) of cobaltous chloride was investigated in Swiss albino mice. The magnitude and duration of rectal temperature depression were dose related. In each case, maximal hypothermia was evident within 30 min after injection. Body temperature depression was noted 30 min after oral, subcutaneous, intraperitoneal, intravenous, and intracerebral administration of cobaltous chloride. Cobalt was most active when administered intracerebrally, suggesting a central component to the thermolytic response. Rectal temperature depression following cobaltous chloride was dependent on the ambient temperature. The time course of the effect of cobaltous chloride on rectal and cutaneous tail temperature was noted. Cutaneous tail temperature depression occurred throughout the rectal temperature response, suggesting that cobalt may decrease heat production. Pretreatment with atropine sulfate, hexamethonium bromide, or nicotine failed to modify the temperature response to cobalt. Chlorpromazine hydrochloride pretreatment resulted in a partial antagonism of cobalt-induced hypothermia, presumably through a mechanism other than cholinergic blockade.