In this study we have evaluated the vaccine potential of a Mycobacterium tuberculosis antigen of the PPE protein family, namely PPE44 (Rv2770c). PPE44-specific immune responses could be detected in mice acutely, chronically and latently infected with M. tuberculosis. Vaccination of mice with a plasmid DNA vaccine coding for PPE44 or recombinant PPE44 protein formulated in adjuvant generated strong cellular and humoral immune responses; immunodominant T cell epitopes were identified. Most importantly, vaccination of mice with both subunit vaccines followed by an intratracheal challenge with M. tuberculosis resulted in a protective efficacy comparable to the one afforded by BCG. Taken together these results indicate that PPE44 of M. tuberculosis is a protective antigen that could be included in novel subunit TB vaccines and that warrants further analysis.