Autologous bone is considered the gold standard for bone regeneration, even if different heterologous bone substitutes have been proposed to overcome the limits related to its use. The aim of this study was to analyze and to compare the molecular events switched on by autologous or heterologous bone graft insertion, focusing on TGFβ1 expression and OPG/RANKL ratio, to analyze resorption process, and estimating graft vascularization, new bone tissue deposition and its mineralization, through VEGF, BSP and SPARC expression evaluation, respectively. Patients needing pre-prosthetic rehabilitation of the posterior maxilla were treated using an equine-derived biomaterial (Group 1) or calvaria autologous bone (Group 2), according to the morphology of the bone defect. Bone graft integration was evaluated on bone samples obtained from the treated areas at the moment of dental implant insertion, by morphological and immunohistochemical analyses for TGFβ1, OPG, RANKL, VEGF, BSP, and SPARC expression. Morphological analysis shows the presence of biomaterial residual granules in Group 1, in parallel to a good integration between graft and host tissue. Moderate TGFβ1 expression is seen in both Group 1 and Group 2. OPG/RANKL ratio appear higher in Group 1; VEGF expression appears very strong in Group 1 and strong in Group 2, while BSP and SPARC expression results weak in Group 1 and moderate in Group 2. Results reveal the good integration between both types of graft and the host tissue, even though autologous graft seems to produce a faster regenerative process, as evidenced by the different expression of the investigated molecules. According to these observations, the clinical use of heterologous particulate equine-derived biomaterial may ensure long-term predictability of implant-prosthetic rehabilitation, comparable to that obtained with autologous bone graft.