Natural killer (NK) cell activity was significantly increased on days 2-6 of infection in the Rickettsia conorii-infected C3H/HeN mice and on day 2 in the Rickettsia typhi-infected C57BL/6 mice. Depletion of NK cell activity utilizing anti-NK1.1 monoclonal antibody enhanced the susceptibility of normally resistant C57BL/6 mice to infection with R. typhi, and depletion of NK cell activity with antibody to asialo GM1 enhanced the susceptibility of C3H/HeN mice to infection with R. conorii. Serum gamma interferon was increased in R. conorii-infected C3H/HeN mice compared with NK cell-depleted, infected mice during the early course of infection. Additionally, the NK cell activating cytokine IL-12 was elevated in the sera of infected mice during the time period representing enhanced NK cell activity compared with uninfected mice. Thus, it appears that NK cells contribute to the early anti-rickettsial immune response, likely via a mechanism involving gamma interferon.