In previous experiments, alpha-MSH (1-13) and ACTH (1-24), which contains the alpha-MSH 1-13 amino acid sequence, were found to reduce fever after central and peripheral administration of low, non-hypothermic doses. Shorter molecules, including alpha-MSH 1-10, had no effect. The idea that the 11-13 amino acid sequence is important to the effect of the parent molecule was tested by giving lysine-proline-valine both centrally and peripherally to rabbits made febrile by IV administration of leukocytic pyrogen. The tripeptide reduced fever after both central (0.5-2.0 mg) and peripheral (2-200 mg) administration. It appears that the 11-13 sequence is part of the message sequence of alpha-MSH with regard to antipyretic activity. However, the lower potency relative to that of the parent molecule suggests that other portions of the molecule are essential to full expression of the antipyretic effect.