[Nle4,D-Phe7]-alpha-MSH has exceptional potency in certain biological assays of alpha-MSH activity such as skin darkening in frogs. However, this analog was equipotent to alpha-MSH in induction of grooming in the rat and had opposite effects on the performance of a visual discrimination task. These results led to the suggestion that distinct differences may exist between the melanocyte and CNS receptors for alpha-MSH. We determined the antipyretic and hypothermic potencies of centrally and peripherally administered [Nle4,D-Phe7]-alpha-MSH, relative to those of alpha-MSH, in the rabbit. Central injections of 40 and 80 ng of [Nle4,D-Phe7]-alpha-MSH caused hypothermia in afebrile rabbits, whereas 20 and 10 ng, which had no effect on afebrile body temperature, caused greater than 40% reduction in leukocytic pyrogen-induced fever. These results indicate that this analog is approximately 10 times more potent in reducing fever than alpha-MSH, making it the most potent antipyretic substance yet described. In contrast, IV administration of 16 micrograms of the analog, an extremely large dose relative to established antipyretic doses of alpha-MSH, elicited weak, variable responses. Since this analog is said to be resistant to degradation by serum enzymes, the contrast between the effects of central and peripheral administration may reflect a limited ability of the analog to cross the blood brain barrier when given IV. Our results do not suggest any distinct differences between the melanocyte receptors for alpha-MSH and those involved with CNS control of temperature. The marked central potency of [Nle4,D-Phe7]-alpha-MSH could result from an increased duration of action and/or a greater affinity for central receptor sites relative to alpha-MSH.