Objective The purpose of this study was to determine in a mouse model whether uterine natural killer (uNK) cell cytotoxic activation induces infection/inflammation-associated preterm labor and delivery. Study Design Wild type or interleukin (IL)-10–/– mice were injected intraperitoneally with lipopolysaccharide on gestational day 14. Mice were either killed for collection of uteroplacental tissue, spleen, and serum or allowed to deliver. Uteroplacental tissue was used for histology and characterization of uNK cells. Results Low-dose lipopolysaccharide treatment triggered preterm labor and delivery in IL-10–/– , but not wild type mice, in a manner independent of progesterone levels. Preterm labor and delivery in IL-10–/– mice was associated with an increased number and placental infiltration of cytotoxic uNK cells and placental cell death. Depletion of NK cells or tumor necrosis factor (TNF)-α neutralization in these mice restored term delivery. Furthermore, TNF-α neutralization prevented uNK cell infiltration and placental cell apoptosis. Conclusion The uNK cell-TNF-α–IL-10 axis plays an important role in the genesis of infection/inflammation-induced preterm labor/delivery.