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Objectives: To compare the 3-year clinical and radiographic outcomes of two different reconstructive surgical management of peri-implantitis using a bone substitute in combination with either concentrated growth factor (CGF) or collagen membrane (CM). Material and methods: Fifty-one patients who had at least one implant presenting peri-implantitis with an intrabony defect were filled with a xenogenic bone grafting material and covered either CGF or CM. Clinical and radiographic assessments were carried out at baseline and postoperative years 1 and 3. Three different composite outcomes were defined to evaluate treatment success at a 3-year follow-up. The effects of possible prognostic indicators on treatment success were identified by using multilevel regression analysis. Results: The changes in probing depth (PD) and radiographic vertical defect depth (VDD) between baseline and year 1 and baseline and year 3 presented significantly greater decreases for the CM group in comparison with the CGF group (p < 0.05). No significant differences between the two treatment modalities were demonstrated regarding treatment success outcomes. History of periodontitis, VDD at baseline, and the number of intrabony defect walls revealed significant impacts on treatment success (p = 0.033; OR = 3.50, p = 0.039; OR = 0.975, and p = 0.024; OR = 7.0 and p = 0.019;OR = 6.0, respectively). Conclusions: CM in combination with a bone substitute seems to have slightly better outcomes compared to the CGF membranes in reconstructive surgical therapy of peri-implantitis. The history of periodontitis, baseline VDD, and peri-implant bone defect configuration could be possible predictors influencing treatment success. Trial registration: ClinicalTrials.gov NCT04769609. Clinical relevance: For the reconstruction of peri-implant bone defects, using a bone substitute in combination with a collagen membrane may show more favorable outcomes. [ABSTRACT FROM AUTHOR]