Background: Histologic studies in animals and humans have provided evidence that the treatment of periodontal defects with EMD promotes healing which is characterized by formation of a new attachment apparatus--namely, new bone, cementum and periodontal ligament. Nevertheless, improvements in clinical outcomes fail to completely restore the periodontium. Considerable interest has focused on the potential of combing EMD with bone replacement grafts to enhance the regeneration. Purpose: The purpose of this paper is systematic review of literature comparing use of EMD alone or in combination with bone replacement grafts in treatment of infrabony defects. Does the addition of a bone replacement graft to EMD improve clinical outcome compared to EMD alone in the treatment of infrabony defects? Methods: An electronic search of the databases MEDLINE and EMBASE was performed without any language limitations as well as hand searches of selected periodicals. Mean differences in clinical outcome measures (clinical attachment level, probing depth, recession, and defect fill) were submitted to a meta-analysis, including assessment for heterogeneity. The meta-analysis was computed using a random-effects model, with α-level set at p ≤ 0.05. Results: The search strategies identified 326 publications, with 10 studies fulfilling qualifications for inclusion in the analysis. A significant overall mean difference was found for defect fill, reflecting greater defect fill when EMD was combined with bone replacement graft compared to EMD treatment alone. No significant differences were found in improvements for mean clinical attachment level and reduction in probing depth. Conclusions: The potential for EMD to support hard tissue formation, as reflected in periodontal defect fill, can be enhanced by the addition of a bone replacement graft. Although a significant improvement in defect fill was shown for combination therapy, the overall mean improvement in defect fill was nonetheless modest in magnitude (≈ 1 mm). Moreover, no evidence was found for a corresponding difference in mean gain in clinical attachment level or probing depth. Thus, the potential benefit of greater defect fill on the therapeutic prognosis of the tooth must be considered in evaluating the cost-benefit ratio for combination therapy using EMD and bone replacement grafts.