CD8+ T lymphocytes play an important role in the control of visceral leishmaniasis in non self-cure mice (e.g. BALB/c). In the present study, the mode of action of CD8+ T cells and their in vivo contribution to immunity was addressed in self-curing C57BL/6 mice. During the course of the experimental infection, CD8+ T cells specific for Leishmania infantum (L. infantum) developed and apoptotic cell death subsequently followed. They exhibited perforin-dependent cytotoxicity and a T(C)1 profile characterized by secretion of IFN-gamma and CC chemokines. Despite evidence for activation of CD8+ T lymphocytes, both intravenous and intradermal infection of beta2-microglobulin deficient C57BL/6 mice with L. infantum showed that these knockout animals had similar parasite loads to their wild-type counterpart. Lymphocytes from the beta2-microglobulin deficient mice produced high levels of IFN-gamma, reflecting a T(H)1 response to the parasite, which was apparently sufficient for the immunologic control of the pathogen. Thus, despite their functional activation, CD8+ T lymphocytes do not appear to play a primary role in parasite restraint in the self-curing mouse model of visceral leishmaniasis, as shown using beta2-microglobulin deficient mice which do not produce functional CD8+ T lymphocytes.