In humans, functional deficiency of alpha-2M is not known, implying alpha 2M is essential for gestational success. Mice, deficient in two members of the alpha-2 Macroglobulin (alpha 2M) family, i.e. alpha-2 macroglobulin (MAM) and murinoglobulin-1 (MUG-1) are viable, fertile and phenotypically normal, unless stressed (Am J Pathol, 155 (1999), 983). Here, we analysed implantation sites in MAM(-/-)/MUG-1(-/-)mice during pregnancy, a strong physiological stressor. Despite some post-implantation fetal loss, mean litter size was comparable to congenic C57Bl/6J (B6) mice, but MAM(-/-)/MUG-1(-/-)pups were significantly lighter and the sex ratio was skewed towards males. Implantation sites appeared histologically normal up to gestational day (gd) 8. By gd 10, extensive over-development of trophoblasts was evident, accompanied by relative deficits in decidua, in the mural mesometrial lymphoid aggregates of pregnancy and in uterine Natural Killer cells. At gd 10-12, decidual spiral arteries were dilated but abnormally cuffed by trophoblasts that extended anomalously, for midgestation, to the myometrial circular smooth muscle. Ultrastructurally, trophoblasts in the mesometrial decidua made intimate contact with endothelial cells that were shedding membrane fragments. These findings demonstrate that alpha 2M, and thereby proteinases and/or cytokines whose bio-availability is regulated by alpha 2M, exert significant decidual regulation on trophoblast invasion.