Aim: To assess whether the use of deproteinized bovine bone mineral (DBBM) and native bilayer collagen membrane (NBCM) improved healing of peri-implantitis-related bone defects at 12 months. Materials and methods: In a multi-centre, randomized clinical trial, 32 individuals received surgical debridement (control group [CG]), and 34 received adjunct use of DBBM and NBCM (test group [TG]). Radiographic defect fill (RDF), probing pocket depth (PPD), bleeding on probing (BOP), suppuration (SUP), recession (REC), cytokines (IL-1β, IL-1RA, IL-6, IL-8, IL-12, IP10, PDGF-BB, TNF-α, VEGF), and patient-reported outcomes (PROs) were evaluated at 3, 6, 9, and 12 months. Results: RDF at the deepest site amounted 2.7 ± 1.3 mm in TG and 1.4 ± 1.2 mm in CG (p <.0001). PPD was reduced by 1.9 mm in TG and 2.3 mm in CG (p =.5783). There were no significant differences between groups regarding reductions of BOP, SUP, REC, cytokines levels, or oral health impact profile (OHIP)-14 scores at 12 months. Successful treatment (RDF ≥ 1.0 mm, PPD ≤5 mm, ≤1/4 site with BOP grade 1, no SUP) was identified in 32% in TG and 21% in CG. Conclusions: DBBM and NBCM resulted in significantly more RDF than debridement alone. No difference was found in any clinical parameters or PROs between the groups. ClinicalTrials.gov Identifier: NCT02375750. © 2021 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd.