Recent cDNA cloning of EMR1 and CD97 suggests the existence of a new group of seven-span transmembrane (7-TM) molecules, likely encoded by a gene cluster on the short arm of chromosome 19. The membrane-spanning region of both molecules is homologous to the secretin receptor (SecR) superfamily, a group of receptors with specificity for mammalian and insect peptide hormones. Unlike members of the SecR superfamily known thus far, EMR1 and CD97 have extended extracellular regions that possess several EGF domains at the N-terminus. We herein describe the organization of the human CD97 gene, which consists of 18 exons expanding approximately 12 kb of DNA. Identical exon-intron positions in the transmembrane region indicate that the CD97 gene has evolved from an ancestral gene of the SecR superfamily. Remarkably, exons encoding the 300 amino acids by which CD97 extends the extracellular part from other members of the SecR group are preferentially separated by introns in phase 1. All three EGF domains are encoded by symmetrical class 1-1 exons, suggesting that exon shuffling to the upstream region of a precursor gene from the SecR superfamily has generated this new type of 7-TM receptor.