Several co-pathogens that pose threats to the fetus during gestation, including human cytomegalovirus (HCMV), may also contribute to mother-to-child transmission (MTCT) of human immunodeficiency virus type 1 (HIV-1). Within endemic settings, associations between maternal HCMV viral load and increased incidence of MTCT of HIV-1 are documented; however, the mechanisms that promote transmission are poorly characterized. Here we demonstrate that HCMV coinfection enhances susceptibility and viral replication of HIV-1 in placental macrophages (Hofbauer cells) in vitro. Consistent with enhanced viral susceptibility, HCMV exposure upregulates CCR5 and CD80 expression on Hofbauer cells. HCMV also significantly induces type I interferon (IFN), proinflammatory cytokines, and antiviral gene expression. Interestingly, we found that HCMV diminishes type I IFN-mediated phosphorylation of STAT2. Collectively, our data suggest that HCMV-induced activation, local inflammation, and antagonism of type I IFN responses in placental Hofbauer cells promote in utero transmission of HIV-1.