Background/Aim: Maxillary sinus floor elevation is a well-established procedure for increasing bone volume in the posterior maxilla, yet the regenerative outcome depends strongly on the choice of grafting material. This clinical study compared a high-temperature sintered xenograft (Bio-Oss®) and a low-temperature processed xenograft (Ti-Oss®) with regard to their regenerative and immunological profiles. Patients and Methods: Eight patients underwent split-mouth sinus augmentation with both materials, and biopsies were retrieved at 6 months after implant placement. Histological, histomorphometrical, and immunohistochemical analyses were performed to assess bone formation, material resorption, and tissue compatibility. Immunohistochemistry was applied to evaluate the local immune response, focusing on macrophage polarization and multinucleated giant cell activity. Quantitative histomorphometry determined the relative areas of newly formed bone, residual graft material, and connective tissue. Results: Histopathological and histomorphometrical analyses demonstrated comparable levels of new bone formation in both groups, confirming reliable osteoconduction. Immunohistochemical evaluation revealed tartrate-resistant acid phosphatase isoform 5a (TRAP5A) expression in multinucleated giant cells adherent to both materials. Interestingly, Bio-Oss® induced a higher proportion of anti-inflammatory (CD163+) macrophages, whereas Ti-Oss® triggered a significantly greater number of pro-inflammatory multinucleated giant cells (CD11c+). Conclusion: These findings indicate that although both xenogeneic substitutes (Bio-Oss® and Ti-Oss®) achieve bone regeneration, they elicit distinct immune responses, which may influence long-term remodeling and graft integration. Consideration of osteoimmunological properties is therefore essential when selecting biomaterials for clinical sinus augmentation. © 2026 The Author(s). This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.