Activation of central melanocortin receptors (MCR) inhibits fever, but the identity of the MCR subtype(s) mediating this antipyretic effect is unknown. To determine whether selective central melanocortin receptor-4 (MC4R) activation produces antipyretic effects, the MC4R selective agonist MRLOB-0001 (CO-His-D-Phe-Arg-Trp-Dab-NH₂) was administered intracerebroventricularly to rats treated with Escherichia coli lipopolysaccharide (LPS, 30 µg/kg ip). Treatment with MRLOB-0001 (150 ng icv) did not lower core body temperature (T_c) in afebrile rats but did suppress LPS-induced increases in T_c and associated decreases in tail skin temperature (T_sk), an indicator of vasomotor thermoeffector function. In contrast, systemic treatment with MRLOB-0001 (150 ng iv) did not produce similar antipyretic effects. Coadministration of the selective MC4R antagonist HS014 (1 µg icv) blocked the antipyretic effects of MRLOB-0001. HS014 alone (1 µg icv) had no significant effect on LPS-induced increases in T_c or decreases in T_sk and in afebrile rats had no significant effects on T_c or T_sk. We conclude that pharmacological activation of central MC4R suppresses febrile increases in T_c and that inhibition of heat conservation pathways may contribute to this effect. These findings suggest that the central MC4R may mediate the long-recognized antipyretic effects of centrally administered melanocortins.