The neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH), a proopiomelanocortin derivative, is a potent modulator of fever, inflammation, and other aspects of the acute-phase response. Alpha-MSH concentrations increase in rabbit plasma after large doses of endotoxin, but it is not known if changes in this potent peptide likewise occur during endotoxemia in humans. The current study performed to assess changes in plasma alpha-MSH during the acute inflammatory response to endotoxin in normal humans. Alpha-MSH was measured in plasma samples obtained over a 5-hour study period in 20 normal human subjects given endotoxin. Plasma adrenocorticotropic hormone (ACTH) and tumor necrosis factor were also measured at the same time points. Endotoxin administration caused fever-related increases in plasma alpha-MSH. Five subjects with a high thermal response to endotoxin (> 2.6 degrees C above baseline) showed a 2- to 4-fold increase in circulating alpha-MSH whereas subjects with low fever (< 2.3 degrees C) did not. Tumor necrosis factor was detected in all subjects after endotoxin, but its peak was significantly less (p < 0.01) in those subjects who had substantial increases in alpha-MSH. Plasma ACTH increased in all subjects given endotoxin, but unlike its 1-13 derivative alpha-MSH, the increases were not commensurate with fever. The data show that challenge with endotoxin causes alpha-MSH release in normal human subjects with high fever. The positive relationship between increases in circulating alpha-MSH and high thermal response together with previous evidence from animal studies suggest that the neuropeptide is an endogenous modulator of host responses.