In CBA/J mice, susceptibility to Mycobacterium tuberculosis (M.tb) is associated with low interferon‐gamma (IFN‐γ) responses to antigens (Antigen 85 (Ag85) and early secreted antigenic target‐6 (ESAT‐6)) that have been defined as immunodominant. Here, we asked whether the failure of CBA/J mice to recognize Ag85 is a consequence of M.tb infection or whether CBA/J mice have a general defect in generating specific T‐cell responses to this protein antigen. We compared CBA/J mice during primary M.tb infection, Ag85 vaccination followed by M.tb challenge, or M.tb memory immune mice for their capacity to generate Ag85‐specific IFN‐γ responses and to control M.tb infection. CBA/J mice did not respond efficiently to Ag85 in the context of natural infection or re‐infection. In contrast, CBA/J mice could generate Ag85‐specific IFN‐γ responses and protective immunity when this antigen was delivered as a soluble protein. Our data indicate that although M.tb infection of CBA/J mice does not drive an Ag85 response, these mice can fully and protectively respond to Ag85 if it is delivered as a vaccine. The data from this experimental model suggest that the Ag85‐containing vaccines in clinical trials should protect M.tb susceptible humans.