Postpartum hemorrhage (PPH) is the leading cause of maternal mortality worldwide. However, the mechanism underlying atonic PPH remains partially elucidated. Multi-omics revealed that differentially expressed proteins and metabolites were enriched in the immune-inflammation pathway in the vaginal blood of patients with atonic PPH. There was a pro-inflammatory immune microenvironment primarily activated by M1 macrophages in the decidua of the patients with atonic PPH, which presented as increased tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-8 levels and affected the contraction of the uterine smooth muscle. Besides, the decidual macrophage of the atonic PPH group exhibited increased oxidative stress. The PPH decidual cell culture medium induced the polarization of peripheral blood monocytes towards M1 macrophages while markedly increasing the levels of reactive oxygen species and superoxide anion radical. Using hydrogen peroxide (H