Adoptive transfer of Toll-like receptor (TLR) 4-stimulated dendritic cells (DCs) induces protective immunity against an ordinarily lethal rickettsial challenge, but the mechanism underlying this protection remains elusive. Therefore, we sought to determine the importance of TLR4 in early immunity to rickettsiae in vivo, particularly that conferred by TLR4-stimulated DCs. Rickettsial growth proceeded logarithmically in mice lacking TLR4 function, whereas in TLR4-competent mice rickettsial growth manifested a lag phase early, suggesting that TLR4 may initiate innate rickettsial immunity. TLR4-competent mice produced significant amounts of interferon (IFN)-gamma on day 1 of Rickettsia conorii infection, which was associated with significant expansion of the population of activated NK cells. Moreover, NK cells from TLR4-competent mice produced significantly higher levels of IFN-gamma and had greater cytotoxic activity than did those from TLR4-deficient mice. Last, adoptive transfer of rickettsiae-exposed, TLR4-stimulated DCs activated NK cells in vivo. Together, these data reveal an important role for DCs in recognizing rickettsiae through TLR4 and inducing early antirickettsial immunity.