Anton Matafonov, Philberta Y. Leung, Adam E. Gailani, Stephanie L. Grach, Cristina Puy, Qiufang Cheng, Mao–fu Sun, Owen J. T. McCarty, Erik I. Tucker, Hiroaki Kataoka, Thomas Renné, James H. Morrissey, Andras Gruber, and David Gailani Abstract The plasma zymogens factor XII (fXII) and factor XI (fXI) contribute to thrombosis in a variety of mouse models. These proteins serve a limited role in hemostasis, suggesting that antithrombotic therapies targeting them may be associated with low bleeding risks. Although there is substantial epidemiologic evidence supporting a role for fXI in human thrombosis, the situation is not as clear for fXII. We generated monoclonal antibodies (9A2 and 15H8) against the human fXII heavy chain that interfere with fXII conversion to the protease factor XIIa (fXIIa). The anti–fXII antibodies were tested in models in which anti–fXI antibodies are known to have antithrombotic effects. Both anti–fXII antibodies reduced fibrin formation in human blood perfused through collagen–coated tubes. fXII–deficient mice are resistant to ferric chloride–induced arterial thrombosis, and this resistance can be reversed by infusion of human fXII. 9A2 partially blocks, and 15H8 completely blocks, the prothrombotic effect of fXII in this model. 15H8 prolonged the activated partial thromboplastin time of baboon and human plasmas. 15H8 reduced fibrin formation in collagen–coated vascular grafts inserted into arteriovenous shunts in baboons, and reduced fibrin and platelet accumulation downstream of the graft. These findings support a role for fXII in thrombus formation in primates.