The in vivo rate of proliferation of Mycobacterium tuberculosis, the causative agent of tuberculosis, has been linked to the rate of progression and severity of disease. Here, we report that deletion of the gene MT2175 (Rv2115c), a putative mycobacterial proteasome-associated AAA-ATPase, leads to a reduction in the growth rate of M. tuberculosis in vitro and in vivo. Despite the reduced growth, the mutant persisted, with slow and gradual clearance in mouse lungs. The mutant elicited reduced levels of interferon-gamma production in the lungs and, when used as an immunizing agent, provided significant protection against challenge with a virulent strain of M. tuberculosis. Expression of the genes lat and MT3159 were highly up-regulated in the mutant. Thus, loss of MT2175 slows both in vitro and in vivo growth rates and compromises the lethality of M. tuberculosis in mice but has a minimal impact on the organism's ability to persist in host tissues.