Visceral leishmaniasis (VL) is associated with increased circulating levels of multiple pro-inflammatory cytokines and chemokines, including IL-12, IFN gamma, and TNF alpha, and elevated expression of IFN gamma mRNA in lesional tissue such as the spleen and bone marrow. However, an immunological feature of VL patients is that their peripheral blood mononuclear cells (PBMCs) typically fail to respond to stimulation with leishmanial antigen. Unexpectedly, it was recently shown that Leishmania specific IFN gamma, can readily be detected when a whole blood stimulation assay (WBA) is used. We sought to define the conditions that permit whole blood cells to respond to antigen stimulation, and clarify the biological role of the IFN gamma found to be released by cells from VL patients. CD4+ T cells were found to be crucial for and the main source of the IFN gamma production in Leishmania stimulated whole blood (WB) cultures. Complement, antibodies and red blood cells present in whole blood do not play a significant role in the IFN gamma response. The IFN gamma production was reduced by blockade of human leukocyte antigen (HLA)-DR, indicating that the response to leishmanial antigens observed in WB of active VL patients is a classical HLA-T cell receptor (TCR) driven reaction. Most importantly, blockade of IFN gamma in ex-vivo splenic aspirate cultures demonstrated that despite the progressive nature of their disease, the endogenous IFN gamma produced in patients with active VL serves to limit parasite growth.