The acute-phase response involves a number of separate physiological components, including induction of acute-phase protein synthesis by the liver. This response can be induced in vivo by administration of the endogenous leucocytic mediator interleukin-1β. A number of in-vivo effects of interleukin-1β have been reported to be mediated by corticotrophin-releasing factor (CRF), including activation of the hypothalamo-pituitary-adrenal axis and induction of fever, and in this report we have examined a possible involvement of CRF in mediating interleukin-1β-induced acute-phase protein synthesis. Interleukin-1β stimulated the elevation of species-specific plasma acute-phase proteins in rats, mice and rabbits. Co-injection of interleukin-1β with the specific CRF receptor antagonist α-helical-CRF9–41 NH2 abolished or attenuated acute-phase protein synthesis induced by interleukin-1β in all three species for up to 12 h after injection. The inhibitory effect of α-helical-CRF9–41NH2 was reduced or absent 24 h after injection. Neutralizing anti-CRF antisera had no effect on acute-phase protein synthesis in the mouse and, paradoxically, potentiated acute-phase protein synthesis induced by interleukin-1β in the rat. These results indicate a possible mediatory role for CRF in regulation of acute-phase protein synthesis, and suggest that CRF may mediate induction of acute-phase protein synthesis by a different mechanism from that involved in regulation of corticotrophin secretion. Journal of Endocrinology (1993) 136, 207–216