The aim of this study is to compare the histomorphometric data of deproteinized bovine bone (DBB) and a fully synthetic bone substitute, poly (lactic-co-glycolic) acid/hydroxyapatite (PLGA/HA) applied for sinus floor augmentation technique. Twelve maxillary atrophic ridges of 8 patients requiring major maxillary sinus floor augmentation were studied; the sites were randomly assigned to the study groups and reexamined at 6 months after grafting using cone beam computed tomography scans and biopsy samples harvested during dental implant placement. Total bone volume, residual graft material volume, and new bone volume were assessed. Measurable biopsies were available from 67% of test sites and 100% of control sites. Poly (lactic-co-glycolic) acid/hydroxyapatite grafts showed no trace of graft material, whereas DBB grafts had a mean graft area of 16.60%. Mean percent of newly formed bone tended to be greater for PLGA/HA than for DBB group. Mean total bone volume percent did not differ significantly: PLGA/HA = 44.45% (CI, 16.42-72.48), DBB = 44.11% (CI, 36.61-51.60). Deproteinized bovine bone and PLGA/HA produced similar total bone volumes. Poly (lactic-co-glycolic) acid/hydroxyapatite appeared to be completely replaced by newly formed bone, whereas DBB presented significant amounts of residual graft material. Poly (lactic-co-glycolic) acid/hydroxyapatite necessitates of more clinical trials to be considered suitable for sinus floor augmentation.