Correlates of protection against tuberculosis are crucial for the evaluation of new vaccine candidates and for the demonstration of their potential efficacy. Such correlates can be proposed on the basis of animal models. In this study, we hypothesized that protection against tuberculosis (TB) induced by bacillus Calmette-Guerin (BCG) correlates with in vitro TB antigen-specific IFN-gamma production. BCG vaccination, known to provide effective protection against TB in animals, was used to investigate the use of in vitro IFN-gamma production as a marker of BCG-induced protection against TB. Our results show that BCG vaccination does provide substantial protection against challenge with Mycobacterium tuberculosis. However, despite previous compelling evidence that Th1 type immune responses are essential for TB immunity, the magnitude of in vitro purified protein derivative (PPD)-specific IFN-gamma production assessed during the course of TB infection did not correlate with protection. This emphasizes the need to identify further correlates of protection, in addition to IFN-gamma, to be used as markers of protective immunity against M. tuberculosis and/or to identify M. tuberculosis antigens inducing IFN-gamma that correlate with protective immunity.