Two different genomic genes for the COUP-transcription factor, COUP-TF II and COUP-TF, have been isolated from a human cosmid genomic library using a [P-32]-labeled cDNA probe. Data obtained from Southern blot analysis of these cosmid clones indicated that two closely related genes exist in the human genome and have a similar genomic organization. The genes are similar in the hormone and DNa binding domains but diverge from one another in the N-terminal region. Using DNA sequencing and polymerase chain reaction (PCR) techniques we have determined that the structure of COUP-TF I consists only of three exons and two introns. Surprisingly, both zinc fingers (i.e., F1 and F2) are located in the first exon. Therefore, COUP-TF 1 is unique among the members of the steroid/thyroid hormone receptor superfamily which have been described to date.