The role of natural killer cells (NK) in murine leprosy was investigated in vivo and in vitro. In a first set of experiments, it was found that IL-2 (interleukin-2) activated NK cells reduced Mycobacterium lepraemurium (MLM) growth in mouse C57BL6/J peritoneal macrophages which had phagocytosed low numbers (MOI of 10 : 1) of MLM ( P<0.0001 at day 20). There was no cytotoxicity exerted by the NK cells against the infected cells in these conditions. Conversely, macrophages heavily infected with MLM (multiplicity of infection of 1000 : 1) were found to be susceptible to lysis by activated NK cells in vitro. In vivo, progressing murine leprosy was associated with a sharp increase in splenic NK cell activity, which was abrogated by treatment with a monoclonal antibody against NK cells. Administration of this monoclonal antibody against NK cells enhanced C57BL6/J mouse susceptibility to mouse leprosy, as seen by a decrease in survival time of mice infected with 10 7 MLM i.v. (81 days vs 110 days, P<0.0005). Overall, these findings suggest that NK cells may play an important role in resistance to leprosy, either by reducing MLM growth in macrophages or by lysing heavily infected macrophages.