Postpartum depression (PPD) is a major public health problem that is experienced by15% of new mothers, but its causes remain unclear. Hormonal fluctuations have been posited to be the most important contributor to PPD, although peripheral immune changes have recently been observed in women with PPD. Little is known about neuroimmune alterations in PPD, thus we used an animal model of PPD incorporating gestational stress, a well-known risk factor, and evaluated the maternal neuroimmune system focusing on the medial prefrontal cortex (mPFC), a key mood-regulating brain region. Pregnant rats underwent chronic variable stress from gestation days (GD) 7–20 or were unstressed and then sacrificed at GD21 or postpartum day(P)8. Brain tissue levels IL-1beta, interferon (IFN) gamma, and TNFalpha, and insulin-like growth factor (IGF)1 transcripts, as well as the phagocytosis-related gene transcripts, CD68, integrin alpha M (ITGAM), complement components (C)3 and C1q, were assessed via qPCR. ELISA was performed on blood to assess peripheral cytokine levels. Gestational stress led to increased expression of IL-1B and IFNy in the mPFC at GD21, and increased expression of ITGAM and C1q, which suggests that stress leads to central inflammation as well as microglia-mediated synaptic remodeling. There was no effect of gestational stress on any genes at PD8, nor stress effects on peripheral cytokines. These data suggest that gestational stress impacts the maternal neuroimmune system, which may thereby contribute to PPD.