alpha-Melanocyte stimulating hormone (alpha-MSH), a 13 amino acid neuropeptide produced by the pituitary gland, was found to markedly inhibit the capacity of exogenously administered interleukin-1 (IL-1) to stimulate the enhanced synthesis of acute-phase proteins and induce neutrophilia in vivo. The administration of ACTH or glucocorticosteroids lacked most of these direct IL-1 inhibitory properties. Therefore, in addition to the previously reported antipyretic action of alpha-MSH, this hormone can also inhibit two other known IL-1 sensitive cellular targets in vivo. Further, alpha-MSH was incapable of modifying the comitogenic influence of IL-1 on murine thymocytes or on an IL-1 responsive T-cell line. These findings suggest a target cell specificity to the IL-1 inhibitory activities of alpha-MSH and fail to support the hypothesis that alpha-MSH functions through competitive inhibition of specific cellular receptors for IL-1.