The transcription factor Rv0081 of Mycobacterium tuberculosis controls hypoxic gene expression and acts as a regulatory hub in the latent phase of tuberculosis (TB) infection. We report here the crystal structure of Rv0081 at 2.9 Å resolution revealing that it belongs to the well-known ArsR/SmtB family proteins. However, unlike other members in this family, Rv0081 has neither a metal-binding domain nor does it possess Cys residues, suggesting an alternate mechanism of gene regulation. Our structural and biochemical analyses suggest the molecular basis for the recognition of self-regulatory DNA sequences and a plausible mechanism of regulation of Rv0081 in the latent phase of TB infection. DATABASE: Structural data are available in the Protein Data Bank under the accession number - 6JMI.