The association between extreme-prematurity births and intrauterine infection emphasizes the importance of understanding the host immune responses against uterine-invading microbes during early pregnancy to the prevention of preterm births. Listeria monocytogenes, a clinically relevant intracellular bacterium, has a predilection for replication at the maternofetal interface during pregnancy. Here, using mice carrying the recessive null osteopetrotic mutation in the colony-stimulating factor-1 (CSF-1) gene, we show that CSF-1-dependent macrophage functions are required for the maternal decidua immune responses against L. monocytogenes infections during early gestation in mice. In the absence of CSF-1, pregnant mice were more susceptible to uterine infection by L. monocytogenes; their inability to control the expansion of colonized bacteria in the pregnant uterus led to decidual cell death, tissue disintegration, and resorption of the developing embryo. However, CSF-1-deficient mice were able to produce significant levels of both Th1 cytokines and neutrophil chemoattractants and to recruit neutrophils to the decidual tissue in response to Listeria infection. Depletion of macrophages in hormonally induced pseudopregnant mice resulted in higher uterine bacterial levels after L. monocytogenes infection. These data suggest that the anti-Listeria responses in the maternal decidual tissue are dependent on CSF-1-regulated macrophages.