In this study the role of natural killer (NK) cells in the course of experimental Leishmania major infection was investigated. NK cells in genetically resistant C57BLl6 mice were depleted by in vivo administration of anti-asialo-GM1 or anti-NK1.l antibodies. A marked exacerbation of the infection was found in the NK-depleted mice within the first two weeks of infection. Both the local tissue swelling and the number of parasites in the lesions were significantly higher than in normal animals. Lymph node cells taken from infected NK-depleted mice released less interferon-y (IFN-y) when cultured in vitro. As an alternate approach we have used poly I : C treatment in order to activate NK cell activity in vivo in BALBlc mice, which are genetically susceptible to L. major infection. Poly I : C treatment led to milder symptoms and to a significantly lower parasite burden in the early course of infection. Lymph node cells from infected and poly I: C-treated BALBlc mice released higher amount of IFN-y in vitro than cells from control mice. These data show that NK cells are active participants in the non-specific phase of anti-leishmania1 activity in the control of parasite multiplication early in the course of L. major infection in mice.