The cell-mediated immune response, with its shift in favour of type-1 over type-2 T-helper cell immune response, is generally regarded as essential to protection against mycobacterial infections. The aim of this study was to evaluate the protective potential of two multicomponent subunit vaccines (MSV-1 and MSV-2) against tuberculosis (TB) based on human immune recognition. MSV-1 consisted of five immunodominant antigens (TB10.4, early secretory antigenic target (ESAT)-6, culture filtrate protein (CFP)-8, CFP-10 and CFP-15) selected from a group of polypeptides, which induced a predominant T-cell response in immune human subjects, whereas MSV-2 consisted of antigens (CFP-11, CFP-21, CFP-22.5, Mycobacterium tuberculosis protein (MPT)-64 and CFP-31) selected from a group of polypeptides which induced a subdominant T-cell response along with the antibody response. Both of these sets of polypeptides were extensively recognised in healthy individuals with significant interferon gamma release compared to the diseased population. In C57BL/6J mice, at the level of the lungs, the order of protective efficacy for the test vaccines was: bacille Calmette-Guerin (BCG)>MSV-2>MSV-1. The protective efficacy of MSV-1 was found to be significantly less than that of MSV-2 and BCG at the level of spleen, whereas that of MSV-2 was comparable to that of BCG. The results of this study indicate that high T-helper cell type 1 response-inducing polypeptides selected on the basis of human immune recognition do not necessarily impart protection during vaccination experiments.