We describe here two human VIP receptor cDNA clones isolated from a jejunal epithelial cell cDNA library. The hIVR8 cDNA encodes a human VIP receptor consisting of 460 amino acids and has seven putative transmembrane domains like other G protein-coupled receptors. When expressed in COS-7 cells, hIVR8 conferred specific [125I]VIP binding sites (dissociation constant = 0.6 nM) with displacement patterns characteristic of the human common VIP/PACAP receptor, i.e., VIP = PACAP-27 > PACAP-38 > helodermin > growth hormone-releasing factor = peptide methionineamide > secretin. It also conferred stimulation of cAMP production by VIP (half-maximal stimulation for 0.5 nM peptide). Another clone, hIVR5, encodes a 495 amino acid VIP receptor-related protein exhibiting 100% homology with the functional VIP receptor (hIVR8) over the 428 amino acids at the C-terminus but a completely divergent 67 amino acid N-terminal domain. When expressed in COS-7 cells, this VIP receptor-related protein does not bind 125I-VIP, although it is normally addressed at the plasma membrane as assessed by immunofluorescence studies.