Hyperthemia was elicited in rats by the subcutaneous injection of 4 mg/kg (+)-amphetamine, 4 mg/kg (+)-p-chloroamphetamine, or 8 mg/kg fenfluramine. This hyperthermia could be abolished by oral pretreatment with 300 mg/kg p-chlorophenylalanine. Cyproheptadine, at a dose of 0.05 mg/kg, completely inhibited the response induced by p-chloroamphetamine, but a dose of 0.4 mg/kg was necessary in the case of amphetamine and fenfluramine. Protection against hyperthermia by p-chloroamphetamine was also provided by chloroimipramine. Hypothalamic turnover of 5-HT was enhanced by all three amphetamines. alpha-Methyltyrosine and disulfiram had no effect on the hyperthemia induced by the amphetamines, FLA-63 seemed even to enhance it. Haloperidol, in the dose range of 0.1 -0.4 mg/kg, attenuated the hyperthermia induced by amphetamine and p-chloroamphetamine, but not that induced by fenfluramine. The results point to a central origin of the hyperthemia induced by amphetamine, p-chloroamphetamine and fenfluramine. In the mediation of this effect, 5-HT and, to a lesser degree, dopamine seem to play an important role.