Several important events occur at the maternal-fetal interface, including generation of maternal-fetal tolerance, remodeling of the uterine smooth muscle and its spiral arteries and glands, and placental construction. Fetal-derived extravillous trophoblasts come in direct contact with maternal decidual leukocytes. Macrophages represent ∼20% of the leukocytes at this interface. In this study, two distinct subsets of CD14(+) decidual macrophages (dMs) are found to be present in first-trimester decidual tissue, CD11c(HI) and CD11c(LO). Gene expression analysis by RNA microarray revealed that 379 probes were differentially expressed between these two populations. Analysis of the two subsets revealed several clusters of coregulated genes that suggest distinct functions for these subsets in tissue remodeling, growth, and development. CD11c(HI) dMs express genes associated with lipid metabolism and inflammation, whereas CD11c(LO) dMs express genes associated with extracellular matrix formation, muscle regulation, and tissue growth. The CD11c(HI) dMs also differ from CD11c(LO) dMs in their ability to process protein Ag and are likely to be the major APCs in the decidua. Moreover, these populations each secrete both proinflammatory and anti-inflammatory cytokines that may contribute to the balance that establishes fetal-maternal tolerance. Thus, they do not fit the conventional M1/M2 categorization.