We have determined the structure of Bacteroides thetaiotaomicron TetX2 at 2.8 Å resolution, and shown that it is a class A flavin dependent oxidoreductase. TetX2 has broad activity against a range of tetracyclines including one of the most recent tetracyclines, tigecycline (Tygacil®). Comparison of TetX2 with that of the weakly homologous Pseudomonas fluorescens para-hydroxybenzoate hydroxylase (PHBH) (21% identity) shows substantial differences among residues at the substrate binding site although FAD is positioned in a similar conformation between the two enzymes and is poised to carry out catalysis.