Abstract Human and mouse TLR4 molecules respond differently to hypo-acylated LPS. The LPS of Coxiella burnetii is hypo-acylated, heavily glycosylated and known to cause a minimal response by human cells. We hypothesized that mice expressing hTLR4 molecules would be more susceptible to C. burnetii infection. Our results suggested that transgenic mice expressing hTLR4 and the human MD-2 adaptor protein (hTLR4/MD-2) generally respond similarly to wild type mice, contrary to our hypothesis. Small differences in bacterial burdens in spleens and/or lungs of infected mice were noted and lung pathology was increased in hTLR4/MD2 compared to wild type mice. Surprisingly, bone marrow chimera experiments indicated that hTLR4/MD-2 expression on non-hematopoietic cells, rather than the target cells for C. burnetii infection, accounted for increased bacterial burden. Very early during infection, cytokines involved in myeloid cell recruitment were detected in the plasma of hTLR4/MD2 mice, but not in wild type mice. This restricted cytokine response was accompanied by early neutrophil recruitment to the lung in hTLR4/MD2 mice. These data suggest that hTLR4/MD-2 may alter early responses to C. burnetii infection. Our results suggest that during C. burnetii infection, the species of origin for TLR4 may be less important than with other pathogens with hypoacylated LPS.