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In the present study the tissue reaction to a synthetic hydroxyl-apatite-based bone substitute material and a xenogenic bovine-based bone substitute material were analyzed. A split-mouth sinus augmentation trial was performed to analyze the capacity of new bone formation within the augmented region together with clinical stability of the inserted implants. Six months after augmentation cylindrical bone biopsies were extracted for histological and histomorphometrical investigation. The cellular reaction, a potential inflammatory response and the ratio of newly formed bone, connective tissue and remaining bone substitute material were evaluated. Further, the amount of multinucleated giant cells and the vascularization within the implantation bed was evaluated. Implants placed in the augmented regions were analyzed clinically two years after placement. Histomorphometric analysis revealed significantly more vessels and a significantly higher vessel fraction in the synthetic study group. Further, significantly more multinucleated giant cells in the synthetic augmentation sides could be detected. In contrast, the differences in fraction of connective tissue, amount of remaining bone substitute and newly formed bone did not show statistical significant differences. Both biomaterials led to a clinical successful implantation in all patients. The results of this study highlight the different cellular reactions of synthetic and xenogenic bone substitute materials. The significant higher amount of multinucleated giant cells within the synthetic implantation bed seems to not affect its biodegradation. Accordingly, it seems that the observed multinucleated giant cells within the implantation bed of the synthetic bone substitute material have characteristics rather similar to foreign body giant cells than to osteoclasts. Keywords: Biomaterial, Bone graft, Histology, Foreign body reaction