Successful pregnancy requires specific maternal immune cells to tolerate and support development of the semi-allogenic fetus. In particular, macrophages have been implicated in suppressing inflammation, promoting immune tolerance, and regulating angiogenesis and vascular remodelling, and may be crucial for successful pregnancy. We hypothesised that macrophages are crucial for placental morphogenesis, specifically through regulating vascular changes required for normal placental development and function. To assess this, a murine macrophage depletion model, CD11b-Dtr, was utilised wherein mice express the diphtheria toxin (DT) receptor (DTR) under the control of the CD11b promoter causing transient ablation of CD11b⁺ cells upon DT treatment. CD11b-Dtr or FVB wild-type females were mated allogeneically to Balb/c stud males or mated syngeneically to CD11b-Dtr or FVB studs, respectively. DT was administered on day 5.5 post coitum (pc) at two doses, 10 ng/g or 25 ng/g. Control mice, CD11b-Dtr females, received PBS. Pregnancy outcomes and placental morphology were assessed on day 17.5 pc (n=10-20 mice per group). Both doses of DT resulted in significant pregnancy failure at day 17.5 pc in both allogeneic and syngeneic groups, compared to <10% failure in control groups. Females treated with 10 ng/g DT revealed growth restriction in foetuses (18% reduction; p ≤0.001) as well as an increase in placental weights (8% increase; p ≤0.001). Immunohistochemical analysis revealed altered structure of the labyrinthine region within the placenta, associated with reduced fetal vasculature and increased trophoblast surface area, indicating a less efficient placenta. In summation, macrophage depletion on day 5.5 pc impairs placental development and compromises fetal health independently of fetal alloantigen exposure. Therefore, tolerance mechanisms are not impeded upon macrophage depletion thus macrophage regulation of tissue remodelling is a determinant of pregnancy success. These results demonstrate significant pregnancy loss when macrophages are depleted potentially owing to the poor vascular development during early placental development.