Interactions between killer cell immunoglobulin-like receptors (KIRs) expressed by maternal decidual natural killer (NK) cells and HLA-C molecules expressed by fetal trophoblast cells affect the extent of trophoblast invasion of the maternal blood supply by unknown mechanisms. This study reports that decidual NK cells expressing the activating receptor KIR2DS1 produce greater amounts of granulocyte−macrophage colony-stimulating factor (GM-CSF) in response to HLA-C2 than NK cells expressing the inhibitory receptor KIR2DL1 or those expressing both KIR2DS1 and KIR2DL1. Trophoblast cells were shown to express GM-CSF receptor-α, and stimulation with GM-CSF increased their migration through fibronectin-coated transwells. The authors suggest that women expressing KIR2DL1, with or without KIR2DS2, who carry a HLA-C2+ fetus will have decreased GM-CSF production in the decidua and hence decreased trophoblast invasion, which correlates with pregnancy disorders such as pre-eclampsia and fetal growth restriction.