Heparin-binding haemagglutinin (HBHA) is a 28-kDa mycobacterial adhesin, composed of three functional domains. Previous work has shown that the C-terminal methylated domain is important for adherence, and it is involved in protective T cell immunity in mouse models. However, the role of the coiled-coil N-terminal domain of HBHA in its overall immunogenic capacity remains elusive. Herein, a comparison of the antibody and cellular immune responses after subcutaneous and intranasal immunization of mice with HBHA (native and recombinant) revealed that the methylation pattern is important but not essential for this property. Subcutaneous immunization of mice with a truncated protein, rHBHADeltaC, which lacks the C-terminal methylated domain, was sufficient to trigger humoral and cellular immune responses to HBHA in mice. Altogether we provide evidence that the coiled-coil N-terminal domain is required for HBHA immunogenicity in vivo.