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<i>Background and objectives</i>: The aim of this systematic review was to assess the available evidence of using enamel matrix derivate in the treatment of peri-implantitis. <i>Materials and methods</i>: Three electronic databases (<i>PubMed</i>, <i>Scopus</i>, and <i>Web of Science</i>) were searched until August 2022 to identify relevant articles. The inclusion criteria consisted in human clinical studies that reported the use of enamel matrix derivate (EMD) in surgical and non-surgical treatment of peri-implantitis. The risk of bias was assessed using Cochrane risk of bias tool for randomized clinical trials (RCTs) and for non-RCTs ROBINS-I tool. <i>Results</i>: Clinical studies included were published between 2012 and 2022 and consisted of two randomized clinical trials (RCTs) for non-surgical therapy and two RCTs, three prospective cohort studies, and one retrospective case series in surgical therapy. Due to the heterogeneity of patients’ characteristics and assessment of peri-implant therapy, statistical analysis could not be achieved. <i>Conclusions</i>: The use of EMD indicated a positive effect on both surgical and non-surgical therapy. However, the available literature is scarce, with low evidence in non-surgical approach and modest evidence in surgical approach using EMD. More RCTs with standardize protocols are necessary to evaluate the efficacy of using EMD in both therapies.