Methylenedioxymethamphetamine (MDMA) produced a significant hyperthermia in rats which was antagonized in a competitive manner by the selective 5-HT2 antagonist, MDL 11,939. The 5-HT antagonist also blocked MDMA-induced neurotoxicity as assessed by the decline in regional 5-HT concentrations observed 1 week later. These two effects of MDL 11,939 were dissociated at higher doses of MDMA where the antagonist still provided virtually complete protection against the neurochemical deficits but only partially attenuated the hyperthermic response. In contrast to the effect of the 5-HT2 antagonist, haloperidol did not alter MDMA-induced hyperthermia but did antagonize its long-term neurochemical effects. Similarly, coadministration of the selective 5-HT uptake inhibitor, MDL 27,777, did not affect the hyperthermia produced by a high dose of MDMA but completely prevented the depletion of 5-HT. When the MDMA-induced hyperthermia was prevented by temporarily maintaining animals at reduced ambient temperature, the neurochemical changes normally observed 1 week later were also blocked. Although these results demonstrate that the drugs tested do not antagonize MDMA-induced neurotoxicity by interfering with its effect on body temperature, they do indicate that MDMA-induced hyperthermia may contribute to the development of the drug's long-term neurochemical effects.