Fetal and neonatal alloimmune thrombo cytopenia (FNAITP) is a life-threatening bleeding disorder caused by maternal antibodies directed against fetal platelet antigens. The immunoreactive epitopes in FNAITP are primarily located in the extracellular regions of the platelet glycoprotein IIIa (beta3 integrin). Here we have established a novel animal model of FNAITP using beta3 integrin-deficient (beta3-/-) mice. We demonstrated first that these mice are immunoresponsive to beta3 integrin; beta3-/- mice transfused with wild-type platelets generated specific anti-beta3 antibodies which were able to induce thrombocytopenia in wild-type mice. Subsequently, beta3-/- female mice (both naive and immunized) were bred with wild-type male mice to recapitulate the features of FNAITP. The titer of generated maternal antibodies correlated with the severity of FNAITP. High titer maternal anti-beta3 anti-bodies caused severe fetal thrombocytopenia, intracranial hemorrhage, and even miscarriage. Furthermore, maternal administration of intravenous immunoglobulin G (IgG) ameliorated FNAITP and down-regulated pathogenic antibodies in both the maternal and fetal circulations.