The placenta harbors a unique microbiome, distinct from other human body sites. A study analyzed placental specimens from 320 subjects to characterize the placental microbiome using 16S rDNA and whole-genome shotgun (WGS) metagenomic approaches. The placental microbiome was found to be composed of nonpathogenic commensal bacteria from the Firmicutes, Tenericutes, Proteobacteria, Bacteroidetes, and Fusobacteria phyla. It showed the highest similarity to the oral microbiome, with Bray-Curtis dissimilarity <0.3. The placental microbiome was associated with a remote history of antenatal infection, such as urinary tract infections in the first trimester, and preterm birth <37 weeks. The microbiome also showed variation based on gestational age and history of maternal infections. The study found that the placental microbiome is likely established by hematogenous spread of oral microbiota, which would take up residence during early vascularization and placentation. The placental microbiome was not structured by vaginal GBS colonization, maternal obesity, or mode of delivery. The study also found that the placental microbiome is associated with preterm birth, and that periodontal disease may be linked to preterm birth. The study used rigorous quality standards and state-of-the-science metagenomics to demonstrate that the placenta harbors a unique low-abundance microbiome. The findings have implications for understanding the role of the placental microbiome in pregnancy and preterm birth.The placenta harbors a unique microbiome, distinct from other human body sites. A study analyzed placental specimens from 320 subjects to characterize the placental microbiome using 16S rDNA and whole-genome shotgun (WGS) metagenomic approaches. The placental microbiome was found to be composed of nonpathogenic commensal bacteria from the Firmicutes, Tenericutes, Proteobacteria, Bacteroidetes, and Fusobacteria phyla. It showed the highest similarity to the oral microbiome, with Bray-Curtis dissimilarity <0.3. The placental microbiome was associated with a remote history of antenatal infection, such as urinary tract infections in the first trimester, and preterm birth <37 weeks. The microbiome also showed variation based on gestational age and history of maternal infections. The study found that the placental microbiome is likely established by hematogenous spread of oral microbiota, which would take up residence during early vascularization and placentation. The placental microbiome was not structured by vaginal GBS colonization, maternal obesity, or mode of delivery. The study also found that the placental microbiome is associated with preterm birth, and that periodontal disease may be linked to preterm birth. The study used rigorous quality standards and state-of-the-science metagenomics to demonstrate that the placenta harbors a unique low-abundance microbiome. The findings have implications for understanding the role of the placental microbiome in pregnancy and preterm birth.