Mycobacterium tuberculosis, the cause of Tuberculosis (TB), infects one third of the world’s population and causes substantial mortality worldwide. In its shortest format, treatment of drug sensitive TB requires six months of multidrug therapy with a mixture of broad spectrum and mycobacterial specific antibiotics, and treatment of multidrug resistant TB is much longer. The widespread use of this regimen worldwide makes this one the largest exposures of humans to antimicrobials, yet the effects of antimycobacterial agents on intestinal microbiome composition and long term stability are unknown. We compared the microbiome composition, assessed by both 16S rDNA and metagenomic DNA sequencing, of Haitian TB cases during antimycobacterial treatment and following cure by 6 months of TB therapy. TB treatment does not perturb overall diversity, but nonetheless dramatically depletes multiple immunologically significant commensal bacteria. The perturbation by TB therapy lasts at least 1.5 years after completion of treatment, indicating that the effects of TB treatment are long lasting and perhaps permanent. These results demonstrate that TB treatment has dramatic and durable effects on the intestinal microbiome and highlight unexpected extreme consequences of treatment for the world’s most common infection on human ecology.