With more than 9 million new infections and 1.5 million deaths claimed every year, tuberculosis remains one of the major scourges of humankind. The only vaccine available against this disease, the attenuated strain Mycobacterium bovis, BCG is effective against severe forms of the disease in infants, but scarcely effective in protecting adults from the pulmonary form of the disease, thus not stopping transmission. Consequently, the development of an effective anti-tuberculosis vaccine is a major goal for improving global health. The most common concept is that a more effective vaccine should include a first immunization with a live vaccine followed by the administration of an acellular boosting vaccine. In this approach, the live vaccine might be either BCG or a different, more efficient attenuated strain. Recently, we showed that a Mycobacterium tuberculosis mutant missing the gene encoding for the extracellular function sigma factor SigE, is strongly attenuated and is able to induce a more effective protection from M. tuberculosis infection compared to BCG in mice. We now further characterize the protective potential of this novel strain in the guinea pig model of tuberculosis. In the guinea pig, it had limited growth but induced a Th1 immune response and was able to significantly reduce the number of colony forming units as well as prolong survival. Taken together these data provide evidence for the use of the M. tuberculosis sigE mutant as the basis for further development as a vaccine against infection.