Coagulation factor XIII is a member of the transglutaminase-family. Transgluaminases cross-link either fibrin monomers in blood coagulation or extracellular proteins in extracellular matrix formation. In early stages of bone healing migration and proliferation of endothelial cells lead to formation of new vessels. The aim of this study was to investigate the angiogenetic activity of plasma factor XIII in bone defects filled with nanoparticulate hydroxyapatite paste. A critical size defect was created in the tibial head of rats which was not filled in group I. In group II the defect was filled with hydroxyapatite paste, and in group III with hydroxyapatite paste enriched with factor XIII. Ten days after surgery angiogenesis in the defects was assessed using immunohistochemistry and confocal laser scanning microscopy. Ac16 antibody was used to detect activation of factor XIII into factor XIIIA. In defects without biomaterial (group I) vessel-rich connective tissue and diffuse distribution of capillaries was observed. In defects filled with pure hydroxyapatite (group II) formation of capillaries was limited to the host bone-hydroxyapatite interface. In contrast, addition of plasma factor XIII to hydroxyapatite (group III) stimulated formation of vessels within the biomaterial. The current study reveals that factor XIII can improve angiogenesis in hydroxyapatite.