The effects on fever of central administration of alpha-melanocyte-stimulating hormone (alpha-MSH) and its antiserum, the specific increase in central concentration of alpha-MSH during fever, and related results indicate that this neuropeptide is important to central nervous system (CNS) regulation of the febrile response. The present experiments were designed to establish whether alpha-MSH is released from septal tissue during fever and, if so, in what temporal course relative to the febrile response. alpha-MSH release at localized push-pull perfusion sites within the septum during fever induced by intravenous interlukin-1 occurred in two basic patterns: prolonged or repeated release over sequential 10-min sample periods or a more discrete pulse largely confined to a single 10-min period. The greatest increases in concentration and the greatest number of increases occurred during the chill phase of fever, when temperature was rising rapidly, rather than during the plateau phase. Such episodic release is similar to that known to occur in neuroendocrine and other physiological systems, and it provides further support for a physiological role of alpha-MSH in CNS control of fever.