We report in this study that the nature of the injected immunogen or infection of mice can change the specificity of antibodies against different epitopes of the mycobacterial 38 kDa antigen. Following Immunization with a selection of 14 peptides, only p65–83 and p285–304 resulted in antibodies binding to the whole antigen, whereas the recombinant antigen induced antibodies to p201–220 and p230–249, which are non-immunogenic following peptide immunization. Killed tubercle bacilli stimulated antibodies exclusively against the N-terminal 1–20 peptide, whilst infection with live tubercle bacilli led to antibodies recognizing non-continuous epitopes, demonstrable by binding to the 38 kDa protein, but to none of the tested peptides. The most striking finding is that protein immunization failed to induce antibodies to p65–83, although this epltope is immunodominant for T cells, irrespective of the mode of sensltizatlon. Since this peptide contains non-overlapping B (69–75) and T (75–81) cell stimulatory cores, it appears that T help dedicated to the adjacent B epltope following peptide Immunization may have shifted in favour of B cells reacting either with distantly located linear epitopes p1–20 and p201–220 following immunization with the whole protein, or to conformational epitopes following tuberculous infection of mice. The mechanisms which can deviate T help from one to another B cell specificity could involve regulation of antigen processing, liable to the nature of the immunogen. The described results suggesting distinct functional pairing between T and B epitopes, but with limited fidelity, may have general implications for the design of subunit vaccines.