We have engineered a scaffold constructed of synthetic octacalcium phosphate (OCP) and porcine collagen sponge (OCP/Col), and reported that OCP/Col drastically enhanced bone regeneration. In this study, we investigated whether OCP/Col would enhance bone regeneration more than beta-tricalcium phosphate (beta-TCP) collagen composite (beta-TCP/Col) or hydroxyapatite (HA) collagen composite (HA/Col). Discs of OCP/Col, beta-TCP/Col, or HA/Col were implanted into critical-sized defects in rat crania and fixed at 4 or 12 weeks after implantation. The newly formed bone and the remaining granules of implants in the defect were determined by histomorphometrical analysis, and radiographic and histological examinations were performed. Statistical analysis showed that the newly formed bone by the implantation of OCP/Col was significantly more than that of beta-TCP/Col or HA/Col. In contrast, the remaining granules in OCP/Col were significantly lower than those in beta-TCP/Col or HA/Col. Bone regeneration by OCP/Col was based on secured calcified collagen and bone nucleation by OCP, whereas bone regeneration by beta-TCP/Col or HA/Col was initiated by poorly calcified collagen and osteoconductivity by beta-TCP or HA. This study showed that the implantation of OCP/Col in a rat cranial defect enhanced more bone regeneration than beta-TCP/Col and HA/Col.