Mycobacterium tuberculosis is an obligate human pathogen capable of persisting in individual hosts for decades. To determine whether antigenic variation and immune escape contribute to the success of M. tuberculosis, we determined and analyzed 22 genome sequences representative of the global diversity of the M. tuberculosis complex (MTBC). As expected, we found that essential genes in MTBC were more evolutionarily conserved than non-essential genes. Surprisingly however, most of 491 experimentally confirmed human T cell epitopes showed little sequence variation and exhibited a lower ratio of non-synonymous to synonymous changes than essential and non-essential genes. These findings are consistent with strong purifying selection acting on these epitopes, and imply that MTBC might benefit from recognition by human T cells.