Tuberculosis (TB) is a re-emerging infectious disease with an increasing public health impact worldwide. Multiple factors hamper an effective global control of TB, for instance, the lack of universally effective vaccines, the increasing poverty in certain areas, massive human displacements, the emergence of multidrug resistance strains which complicate already established therapeutic schemes, among others. Dendritic Cells (DC) are sentinels of the immune system strategically located at the interface with the external microenvironment, such as the lining mucosae and epithelia. In all these tissues of permanent antigenic contact like the skin, DCs capture antigens (Ags), get stimulated, and migrate towards the nearest regional lymphoid tissue. There, the encounters between these Ag-loaded matured DCs and infrequent specific T lymphocytes are greatly facilitated, thus initiating effector T cell responses. As mycobacterium tuberculosis is an intracellular pathogen, generating T cell immunity is the most important mechanism to control this infection. However, it is still unknown how, if at all, DCs in the skin participate during human cutaneous tuberculosis (CuTB), either in the pathogenesis or the protection. Thus, we wanted to initiate exploratory studies about this intriguing disease. From 23 patients clinically and histologically diagnosed with CuTB, we selected eight skin samples positive for Mycobacterium tuberculosis by PCR and assessed in situ cutaneous DCs by MHC-II (DR), CD1a, and Langerin expression. Unlike healthy control subjects, CuTB patients unexpectedly showed significantly more (p <0.001) and bigger (p <0.001) epidermal DCs. Keratinocytes were enlarged too and some appeared to be MHC-II+ and CD68+, suggesting chronic stimulation. Although CuTB samples exhibited remarkable epidermal widening (acanthosis), increased DC frequency seemed independent from it since the correlation was low (0.45). While in normal skin, CD1a+ and Langerin+ DCs were confined to the epidermis, in CuTB they were readily seen within the dermis. Intriguingly, only CuTB samples showed DCs towards the external (corneal) layers. The excess of epidermal DCs, some of them aberrantly and superficially located, indicates either altered local DC colonization or trafficking during CuTB. Likewise, enlarged, and seemingly activated MHC-II+/CD68+ keratinocytes, might trigger inadequate immune responses as keratinocytes may function as non-professional antigen-presenting cells. It is thus conceivable that: a) the local handling and b) the subsequent ferrying and presentation of mycobacterial Ags into regional lymphoid tissues (both crucial functions of skin DCs) might be hampered during CuTB, ultimately interfering with establishing with the skin, the effective T cell responses needed to combat and clear this intracellular infection. © 2012 Nova Science Publishers, Inc. All rights reserved.