Successful craniofacial reconstruction needs both a well-known and a reliable reconstruction material. However, there is often a lack of long-term knowledge of the tissue reactions and healing process in the human body. In this study, frontal sinus obliterations with bovine bone natural hydroxyapatite derivative (BHA), synthetic bioactive glass S53P4 (BAG) and hydroxyapatite cement (HAC) were investigated with clinical, histologic, scanning electron microscopic (SEM) and energy dispersive x-ray analysis (EDXA) 27, 12 and 3 years postoperatively. The aim was to determine the long-term clinical biocompatibility of the used materials. Histologic studies revealed bone formation with BHA particles and lamellar bone with BAG granule remnants in close contact to the new bone formation. In HAC reconstruction there was scattered fibroconnective tissue growth without new bone formation in the surface of HAC implantation. Neither foreign body reaction nor any abnormal findings were seen. SEM studies revealed a CaP layer on the surface of BAG granule remnants. In EDXA studies, composition profiles showed Ca-, P- and Si- rich layers on the BAG granule surface. No differences were found in CaO and P2O5 levels between BHA granules and HAC implantation and the surrounding bone. All investigated biomaterials were well tolerated in long-term applications.