CmtR is a repressor of the ArsR-SmtB family from Mycobacterium tuberculosis that has been shown to sense Cd(II) and Pb(II) in Mycobacterium smegmatis. We establish here that CmtR binds cooperatively to multiple sites in M. tuberculosis DNA and protects an unusually long 90 bp AT-rich sequence from -80 bp to +10 with respect to its own initiation codon. CmtR interacts with four hyphenated imperfect inverted repeats matching the consensus sequence TA/GTAA-N(4-5)-TT/GATA in the protected region. SDS-PAGE and formaldehyde crosslinking experiments showed that CmtR forms higher-order oligomers (up to an octamer). The oligomerization of CmtR is in agreement with the cooperative binding of CmtR to multiple sites on DNA. Two promoters transcribe cmtR, and the major promoter physically overlaps with CmtR binding sites. Autorepression of CmtR is mediated by cooperative interaction of CmtR with multiple sites on DNA that occlude the major operon promoter. The combined results of a GFP reporter assay, an electromobility shift assay and a DNase I footprinting experiment establish that Cd(II), not Pb(II), disrupts the interaction of CmtR with DNA to de-repress transcription of the cmtR-Rv1993c-cmtA operon in M. tuberculosis.