The aim of this work was to investigate the morphological structure and the expression of vascular endothelial growth factor (VEGF) after maxillary sinus augmentation through equine and porcine bone substitutes in humans. Ten patients showing edentulous posterior maxilla underwent maxillary sinus augmentation through particulate equine bone substitute and 10 patients through particulate porcine bone substitute. At the moment of implants insertion, 6 months after grafting, bone specimens were withdrawn and processed for morphological and immunohistochemical analyses. Notwithstanding the almost comparable clinical performances of both bone substitutes, histological results showed a better integration when an equine bone substitute was used compared to a porcine one. In particular, evident signs of particles resorption were observed in equine bone substitute group specimens compared to porcine ones. Immunohistochemical analysis showed a statistically significant increase of VEGF expression in equine compared to porcine bone substitute group specimens. These results showed both bone substitutes to achieve comparable clinical performance, indicating their successful use for bone regenerative procedures. However, in the same experimental time, equine group specimens showed evident resorption phenomena, whereas no or little signs of resorption were evident in the porcine group specimens. However, a more rapid and intense vascularization was achieved in equine bone substitute group, as demonstrated by immunohistochemical analysis for VEGF expression. Even if differences in vascularization significantly affect the clinical performance of a heterologous bone substitute, its ability to be resorbed is also very important in influencing long-term integration and long-term predictability of implant-prosthetic rehabilitation in regenerated sites.