NK cells are critical components in innate immunity, yet little is known about their migration and proliferation during infection. In this report we study the early NK response toward vaccinia. We observed NK migration into the infected peritoneum as early as 6 h after vaccinia inoculation. Interestingly, although NK trafficking to the infected peritoneum depended on Gαi protein-coupled receptors, trafficking to other tissues (including lung, liver, spleen, and bone marrow) did not. We found that despite a dramatic increase in NK numbers at the primary site of infection, their in situ proliferation was low compared with that at other tissue locations. These features are similar to those found for Ag-experienced T cells, suggesting similar patterns of trafficking and proliferation for these lymphocyte subsets.