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The objective of this systematic review was to assess the clinical efficacy of the tooth-bone graft as a bone substitute in the oral and maxillofacial region in humans as compared to ungrafted sites and other bone substitutes.Databases were electronically and manually searched up to January 2017 to identify animal and human studies and a risk of bias analysis and descriptive statistics was performed.Eighteen animal controlled trials (401 animals), 4 human randomized controlled trials, 1 cohort study, and 3 controlled trials (184 patients) were included. Graft processing was highly heterogeneous. 71.42% clinical and 55.56% animal studies reported no significant difference between tooth-bone graft and controls. Histologically, a dentin-bone complex was reported. A low risk of bias was noted in only 50% of the randomized controlled trials and 63.33% animal study entries. An independent analysis of 6 high-quality case reports (350 patients) revealed complications in 18.86% cases.Tooth-bone graft demonstrated no added benefits over conventional graft materials. Absence of standardized processing and heterogeneous study results limit its use in clinical practice. Until long-term studies determine its success, clinicians are recommended to use it with caution because of high variability in resorption time (2–24 weeks) and a risk of graft dehiscence (12.96%–34.38%).