Activation of central melanocortin receptors (MCR) inhibits fever but can also stimulate thermogenesis, and the mechanisms involved are unknown. To determine whether the long-recognized antipyretic effect of exogenous α-MSH is mediated by the melanocortin-4 receptor (MC4R), and what thermoeffector systems are involved, we tested the effects of intracerebroventricular (icv) injection of α-MSH on lipopolysaccharide (LPS, 30 μg/kg ip)-induced fever in rats, in the presence and absence of the selective MC4R antagonist HS014. Treatment with α-MSH (1 μg, icv) suppressed LPS-induced increases in core body temperature ( T c), whereas a lower dose (300 ng) was ineffective. Nevertheless, both α-MSH doses effectively inhibited LPS-induced peripheral vasoconstriction, the principal heat-conserving thermoeffector, as determined by changes in tail skin temperature ( T sk). This implies that the net antipyretic effect of α-MSH cannot be accounted for solely by modulation of heat loss effectors, but also involves other mechanisms. Surprisingly, central MC4-R blockade by coinjected HS014 (1 μg) not only prevented, but reversed the effect of α-MSH (1 μg) on T c, thus resulting in augmented LPS-induced fever. In afebrile rats, α-MSH infusion caused a modest transient increase in T c that was blocked by coinjected HS014, but was not accompanied by altered T sk. Overall, the results support the hypothesis that the MC4R mediates the antipyretic effects of α-MSH. Paradoxically, in the presence of pharmacological MC4-R blockade during fever, exogenous α-MSH can exacerbate fever, probably by acting via other central MCR subtype(s). In normal animals, centrally injected α-MSH exerts a hyperthermic effect that is mediated by the MC4R, consistent with recent evidence that MC4R activation promotes energy expenditure in normal states through stimulation of thermogenesis.