{17??-Hydroxysteroid} dehydrogenase type 4 {(17??-HSD4)} is the most unusual among human {17??-HSDs.} It is characterized by a multidomain structure, in which the dehydrogenase domain is fused to a hydratase and a lipid transfer domain. {17??-HSD4} not only inactivates estradiol by conversion to estrone but its three protein domains also participate in successive steps of peroxisomal ??-oxidation of long- and branched-chain fatty acids. We have compared the genomic structure of human {17??-HSD4} and several homologous genes from lower animals and fungi. Our data suggest an evolutionary scenario for the three protein domains and indicate a highly dynamic history of the enzyme but also a very high conservation of multifunctionality. This suggests that the main function of human {17??-HSD4} is still its involvement in fatty-acid metabolism, while steroid conversion is only a secondary and possibly minor activity in vivo. Copyright ?? 2001 Elsevier Science Ireland Ltd.