Natural killer (NK) cells have been implicated in the natural protection and healing of leishmaniasis by their ability to secrete the macrophage activating cytokine interferon (IFN)gamma. Previous studies have demonstrated that early production of interleukin (IL)-12 triggers IFN gamma secretion by NK cells. Here we report that live Leishmania promastigotes (the form that is injected by the vector) can directly induce human peripheral blood NK cells from healthy donors to IFN gamma secretion in the absence of IL-12 and professional antigen presenting cells. Killing of promastigotes abolishes this property. This novel mechanism of activation of the innate immune response may be relevant for establishment of infection and thus also the design of vaccines against leishmaniasis.