The Old Yellow Enzyme from Ferrovum sp. JA12 (FOYE) displays an unusual thermal stability for an enzyme isolated from a mesophilic organism. We determined the crystal structure of this enzyme and performed a bioinformatic characterization to get insights into its thermal stability. The enzyme displays a tetrameric quaternary structure, but unlike the other tetrameric homologs, it clusters in a separate phylogenetic group and possesses unique interactions that stabilize the oligomerization. The thermal stability of this enzyme is due mainly to an unusually high number of intramolecular hydrogen bonds. Finally, this study provides a general analysis of the forces driving the oligomerization in Old Yellow Enzymes.