At term, amniotic fluid contents may mediate the onset of labor through the activation of amniotic fluid macrophages and their migration into the myometrium. To test this concept, the authors examine the histological changes that occur in myometrial biopsies at term prior to (n = 53) and during (n = 15) labor. Biopsies were stained with an antimacrophage antibody, anti-CD34 (endothelial cells), and anti-caspase 3 (apoptotic cells). The samples showed a variable inflammatory infiltrate of neutrophils and macrophages, with a greater infiltrate in the samples obtained during labor (P<.001, Fisher exact test). Prior to labor, there were prominent changes in the myometrial fibers that reflected shearing, shrinkage, edema, and particularly apoptosis; endothelial cells of thin-walled vessels prominent in the biopsies displayed marked nuclear biotinylation, and the vascular lumen contained fibrin and platelet thrombi, microparticles, desquamated endothelial cells, amniotic squamous cells, and mucoid material. These changes were also present in samples obtained during labor. In an additional 10 patients in labor with male fetuses, myometrial samples were examined for the presence of macrophages carrying a Y chromosome indicative of a fetal origin, but none were observed. These findings suggest that endothelial cell damage and amniotic fluid embolism are very common at term prior to clinical labor and provide a mechanism by which surfactant protein A and phospholipids present in the amniotic fluid may access myometrial cells and provoke the inflammatory response that occurs during parturition. The authors' studies give no support to the suggestion that fetal macrophages might invade the human myometrium at term.