Pregnancy outcome is severely compromised by intrauterine infections and inflammation. Although the pregnant uterine microenvironment is replete with innate immune cells and TLR expression, the mechanisms that facilitate adverse effects of their activation are largely unknown. In this study, we mimic the activation of TLR9 with its pathogenic ligand hypomethylated CpG and demonstrate that IL-10 proficiency protects against CpG-induced pregnancy complications. We show that fetal resorption and preterm birth are rapidly induced in IL-10(-/-) mice by low doses of CpG (approximately 25 microg/mouse) when injected i.p. on gestational day 6 or gestational day 14, respectively. In contrast, wild-type mice failed to experience such effects at comparable doses, but pups born at term displayed craniofacial/limb defects in response to higher doses (approximately 400 microg/mouse). Pregnancy complications in IL-10(-/-) mice were associated with unexpected and robust TLR9-triggered activation and amplification of uterine neutrophil and macrophage subpopulations followed by their migration to the placental zone. Furthermore, a dramatic increase in serum levels of mouse KC and TNF-alpha production by uterine F4/80(+) cells, but not uterine NK or Gr-1(+)CD11b(+) cells, was observed. Depletion of F4/80(+) macrophages or neutralization of TNF-alpha rescued pregnancy to term. Our results have important implications for IL-10-mediated "uterine tolerance" against CpG-driven innate immune activation.