A variant of the human corticotropin-releasing factor receptor has been characterized. The variant has a 40-amino-acid deletion in the amino-terminal domain of the receptor and is the only form of this receptor detectable in the individual from which it was isolated. In contrast to the high affinity expressed by the normal human CRF receptor, the receptor variant fails to bind [125I]oCRF with high affinity in transfected COS-1 cells. High concentrations of human CRF are required to elevate intracellular cAMP levels in the cells transfected with the variant receptor; EC50 values of 301 and 0.55 nM were obtained in cell expressing the receptor variant and normal CRF receptors, respectively.