The present study was designed to examine 1) functional interactions between 5-HT1A and 5-HT2A/C receptors in thermoregulation in rats and 2) the specific involvement of 5-HT2A and 5-HT2C receptors in such interactions. The 5-HT2A/C receptor agonist DOI (0.025-1.6 mg kg−1, subcutaneously) produced a dose-dependent hyperthermia in rats, which was enhanced by addition of either of two 5-HT1A receptor antagonists, (−)-pindolol (0.5-1.0 mg kg−1, subcutaneously) or WAY-100,635 (0.1-0.4 mg kg−1, subcutaneously). Furthermore, the DOI-induced hyperthermia was counteracted by pretreatment with the 5-HT1A receptor agonist 8-OH-DPAT (0.05 mg kg−1, subcutaneously). The hyperthermia produced by DOI, alone or in combination with WAY-100,635, was fully antagonized by pretreatment with the 5-HT2A/C receptor antagonist ritanserin (1.0 mg kg−1, subcutaneously), as well as with the selective 5-HT2A receptor antagonist amperozide (2.0 mg kg−1, subcutaneously). The present results provide evidence for functional interactions between 5-HT1A and 5-HT2A receptors in temperature regulation in rats, and also suggest an important role for postsynaptic 5-HT2A receptors in the mediation of DOI-induced hyperthermia.