We have investigated the induction and role of natural killer (NK) activity in lymphocytic choriomeningitis virus (LCMV)-infected β2-microglobulin-deficient (β2m-) mice. We demonstrate that LCMV infection is more effective than polyinosinic:poiycytidylic acid (poly I:C) at stimulating NK activity in β2m- .In addition, β2m- NK cells respond poorly to in vitro treatment with IL-12. The target specificity of the virally induced NK cells is similar to that previously reported for chemically induced β2m- NK cells. In both cases they can lyse YAC-1 tumor cells but are unable to kill β2m- orβ2m+ T cell blasts. We have also found that the time course of induction of NK and cytotoxic T lymphocyte (CTL) activity by LCMV in β2m- mice is delayed compared with normal mice. Maximal NK and CTL activity is attained at day 8 and 10 post-infection respectively in β2m- compared with day 4 and 6-8 in B6 mice. Whereas normal mice die ̃7 days following intracranial infection with LCMV, the course of disease in β2-m mice is protracted and characterized by a marked loss of body weight. We show that although the CD4+ CTL response in these mice is intimately involved in mediating weight loss, the virus-induced NK cells do not appear to play a role in the disease. © 1995 Oxford University Press.