The aim of the present study was to evaluate the effects of systemic EPO treatment alone or in combination with xenogenic bone graft augmentation on bone regeneration. Eleven adult male Sprague-Dawley rats were used in the present study. Rats were subjected to bilateral 5 mm critical size bone defects on the parietal bones under general anaesthesia. Right parietal bone defects were augmented with xenogenic bone graft and left parietal bone defect was left empty. Rats were randomly assigned for one of the two groups. One group of rats received (i) vehicle (n = 6) and other group received (ii) EPO (500IU kg/day) (n = 5). EPO treatment was continued for 28 days. Vascularization was analysed by immunohistochemical staining of CD31 (PECAM-1) and new bone formation was histomorphometrically evaluated. Xenogenic graft augmentation enhanced bone formation and vascularization significantly in either vehicle or EPO treated groups (p < 0.05). Histomorphometric results of angiogenesis was similar in the EPO treated group and the control group. However, angiogenesis was significantly higher in the combination of systemic EPO treatment with graft augmentation than graft augmentation alone (p < 0.01). Graft augmentation for treatment of critical size bone defects seems essential for proper bone healing. Results of the present study suggest that EPO potentiates the regenerative processes of augmented bone defects. (C) 2018 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.