Purpose: The aim of this systematic review was to investigate which material is the most effective bone substitute for alveolar bone healing by evaluating histomorphometric outcomes after healing of postextraction sockets in humans. Materials and Methods: A manual and electronic search (PubMed, EMBASE, Cochrane Library) was performed using a search string prepared ad hoc. Data were statistically analyzed by calculating weighted mean percentage of new bone formation (primary outcome) and weighted mean percentage of residual biomaterial, soft/connective tissue, and nonmineralized tissue (secondary outcomes) in the biopsies. A meta-analysis of the included randomized controlled trials (RCTs) was performed. Results: A total of 802 papers were screened. After application of the inclusion and exclusion criteria, a total of 40 articles were included in the quantitative synthesis while 11 were included in the meta-analysis of comparative studies. The evaluation of comparative studies with empty sites as control showed that bovine bone could lead to a lower proportion of new bone formation compared to sites left to heal spontaneously (P .00001). Magnesium-enriched hydroxyapatite and porcine bone showed a significantly higher percentage of new bone compared to control sites (P .00001). Grafting with an allograft did not lead to a higher percentage of new bone formation in comparison with control sites (P = .09). Conclusion: There was no evidence for the superiority of a given biomaterial over the others in terms of new bone formation. While calcium sulphate and beta-tricalcium phosphate resorbed faster than other biomaterials, xenografts showed a lower resorption rate than allografts. Comparative studies suggested that bovine bone was related to a lower proportion of new bone volume compared to sites left to heal spontaneously, while porcine bone and magnesium-enriched hydroxyapatite were related to higher new bone volume. Allograft was not related to higher new bone volume than sites healed without any biomaterial.