We have investigated the influence of early innate immune resistance mechanisms on infection with the intracellular bacterium Listeria monocytogenes in rats. Rats were injected i.v. with various amounts of Listeria and the number of bacterial colonies in the spleen was determined at different time points after infection. A bacterial dose as low as 2 × 104 cells gave reproducible infection within the spleen. Athymic nude rats lacking normal T cells but with a robust NK cell repertoire for MHC antigens were more resistant to bacterial replication within the spleen than were normal littermate rats and eliminated the infection within 3 days. In vivo depletion of NK cells, or NK subpopulations expressing Ly49 receptors, increased the bacterial load in the spleen, indicating that these cells were important in the initial control of Listeria infection. An increased frequency of Ly49 expressing NK cells in Listeria-infected rats further supported this notion. As several rat strains, unlike mice, display a large repertoire of MHC-recognizing activating Ly49 receptors, these observations raise the interesting possibility that NK cells may recognize alterations in the MHC-I molecules on Listeria-infected cells leading to their elimination before the adaptive immune system comes into play.