Leishmania braziliensis is a parasite that can induce at least two clinical forms of leishmaniasis in humans: cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML). In humans, the specific mechanisms that determine which form will develop following infection are not well established. In this study, peripheral blood mononuclear cells from 17 CL and 9 ml patients were compared both ex vivo and after culture with soluble leishmania antigen (SLA). Patients with ML presented a higher frequency of activated T cells as measured by ex vivo frequencies of (CD4+)(CD69+), (CD4+)(CD28-), (CD4+)(CD62L-) and (CD8+)(CD69+) than those with CL. Moreover, after stimulation with SLA, patients with ML presented a higher frequency of TNF-alpha-producing CD4+ and CD14+ cells than CL individuals. While CL patients displayed a positive correlation between the frequency of IL-10 and TNF-alpha-producing monocytes, the ML patients did not. This lack of a positive correlation between IL-10-producing and TNF-alpha-producing monocytes in ML patients could lead to a less controlled inflammatory response in vivo. These results corroborate with a model of an exacerbated, unregulated, immune response in ML patients and point to key immunomodulatory leucocyte populations and cytokine networks that may be involved in the development of immunopathology in ML patients.