We have previously characterized the first human NAD(+)-dependent short chain dehydrogenase capable of oxidizing all-trans-retinol and androgens, and found only in the liver and skin. In a search for related human enzymes, we identified a partial open reading frame, which exhibited >60% sequence identity to human RoDH-4. The full-length cDNA for this enzyme was determined in our laboratory by 5'-RACE PCR and was found to be identical to the recently reported novel type of oxidative human 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD). Analysis of the genomic structure revealed that the gene for RoDH-like 3alpha-HSD has four translated exons and, possibly, a fifth exon that codes for the 5'-untranslated region. The gene for RoDH-4 appears to have only four exons. The positions of exon-intron boundaries and the sizes of the protein coding regions are identical in 3alpha-HSD and RoDH-4. Moreover, both genes are mapped to chromosome 12q13, and are located in a close proximity to each other. Both genes appear to have satellite pseudogenes. Thus, RoDH-4 and 3alpha-HSD genes share similar structural organization and cluster on human chromosome 12, near the gene for 11-cis retinol dehydrogenase.