Autoimmune antibodies to 2-glycoprotein I (2GPI) have been proposed to be clinically relevant because of their strong association with thrombosis, miscarriage, and thrombocytopenia. By using a homologous recombination approach, 2GPI-null mice were generated to begin to understand the physiologic and pathologic role of this prominent plasma protein in mammals. When 2GPI heterozygotes on a 129/Sv/C57BL/6 mixed genetic background were intercrossed, only 8.9% of the resulting 336 offspring possessed both disrupted alleles. These data suggest that 2GPI plays a beneficial role in implantation and/or fetal development in at least some mouse strains. Although those 2GPI-null mice that were born appeared to be relatively normal anatomically and histologically, subsequent analysis revealed that they possessed an impaired in vitro ability to generate thrombin relative to wild type mice. Thus, 2GPI also appears to play an important role in thrombin-mediated coagulation. ; Yonghua Sheng, Stephen W. Reddel, Herbert Herzog, Ying Xia Wang, Tim Brighton, Malcolm P. France, Sarah A. Robertson and Steven A. Krilis