To explore the reported contradictory osteogenic capacity of platelet-rich plasma (PRP), the aim of the study was to examine and compare the bone regenerative effect of: PRPs of different species (rat, goat, human); human bone graft (HB) vs. HB combined with human PRP (HB+hPRP); and HB+hPRP vs. synthetic hydroxyapatite-tricalcium phosphate bone substitute combined with hPRP (HA/TCP+hPRP). For this purpose, 72 implants, divided into 6 groups (n=6) were inserted in critical-sized defects of immunodeficient rats. After 2 and 4 weeks, descriptive and quantitative histological, and micro-CT analyses were performed on the specimens. Rat and goat PRP combined with HA/TCP did not enhance bone regeneration compared with HA/TCP. In contrast, human PRP combined with HA/TCP resulted in significantly increased bone fill compared to HA/TCP. The addition of human PRP to human bone graft increased significantly the amount of newly formed bone after 2 weeks. HB+hPRP demonstrated enhanced bone healing compared to HA/TCP+hPRP. In conclusion, rat and goat PRP had no effect on bone formation. Human PRP improved the initial osteogenic response of human bone graft. Human PRP combined with human bone graft had better osteogenic capacity than human PRP combined with synthetic bone substitute.