Thrombotic thrombocytopenic purpura (TTP) is the prototypical microangiopathy characterized by disseminated microthromboses, hemolytic anemia, and ultimately organ dysfunction. A link with deficiency of the von Willebrand factor (VWF) cleaving protease (ADAMTS13) has been demonstrated but additional genetic and/or environmental triggers are believed to be required to incite acute illness. Here we report that four days of ADAMTS13 functional inhibition is sufficient to induce TTP in the baboon (Papio ursinus), in the absence of inciting triggers, since injections with an inhibitory monoclonal antibody (mAb) consistently (n=6) induced severe thrombocytopenia (<12x10(9)/L), microangiopathic hemolytic anemia with schistocytes and a rapid rise in serum lactate dehydrogenase. Immunohistochemical staining revealed the characteristic disseminated platelet-and VWF-rich thrombi in kidney, heart, brain and spleen but not lungs. Prolonged inhibition (14 days, n=1) caused myocardial ischemic damage and asplenia but not death. Control animals (n=5) receiving equal doses of a non-inhibitory anti-ADAMTS13 mAb remained unaffected. Our results provide evidence for a direct link between TTP and ADAMTS13 inhibition and for a mild disease onset. Furthermore, we present a reliable animal model of this disease as an opportunity for the development and validation of novel treatment strategies.