Introduction: The aim of the presented research was to analyse and compare the tissue reaction to different xenogeneic bone substitute materials (Bio-Oss®, BO and BEGO Oss®, BGO) of different processing techniques and material-specific characteristics in vivo. Materials and Methods: Two bone substitute materials were implanted subcutaneously in CD-1 mice for up to 60 days. Tissue formation, implant bed vascularisation and the formation of multinucleated giant cells were investigated histologically and histomorphometrically. Results: Both bone substitute materials showed good integration within the peri-implant tissue and no signs of adverse effects. Both groups presented an increasing vascularisation over the whole study period. Within the implantation bed of the bone substitute of low sintering temperature (BO), few multinucleated giant were obvious on the surface of small sized bone substitute granules in the early integration period, while the tissue reaction to the bigger granules at later stages consisted mainly of mononuclear cells. In contrast, the tissue reaction to the bone substitute material of high sintering temperature (BGO) consisted of a biomaterial surface associated multinucleated giant cells. Discussion: The tissue reactions to the low and high sintering temperature bone substitute materials investigated showed distinct differences, mainly in the formation and migration of multinucleated giant cells. As both biomaterials have the same origin, the observed differences seem to be related to the different processing techniques and the resulting different physico-chemical structures. Keywords: bone substitute materials, xenogenic, foreign body cell reaction, multinucleated giant cells