This multi-center, randomized clinical trial compared the long-term outcomes of guided bone regeneration (GBR) with open flap debridement (OFD) in treating peri-implantitis-related bony defects with ≥3 osseous walls over 36 months. The study aimed to evaluate the healing potential of GBR using a deproteinized bovine bone mineral (DBBM) graft and native bilayer collagen membrane (NBCM) compared to OFD without the use of graft materials. Sixty-six individuals diagnosed with peri-implantitis were randomly assigned to either GBR (34 patients) or OFD (32 patients). The OFD group served as the control, where inflamed tissue was removed and the implant surface decontaminated using 3% hydrogen peroxide, but no bone graft was placed. The GBR group received DBBM and NBCM for defect reconstruction. Radiographic defect fill (RDF), probing pocket depth (PPD), bleeding on probing (BOP), suppuration (SUP), mucosal recession (MREC), and patient-reported outcomes (PROs) were assessed over the study duration. Post-surgical care included azithromycin, ibuprofen, and chlorhexidine rinses. The study involved baseline assessments, surgical interventions, and follow-ups at 6, 12, and 36 months. Supportive peri-implant therapy was provided every 3 months during the additional 24-month follow-up. Primary outcome was RDF at 36 months. Secondary outcomes included PPD, BOP, SUP, MREC, and PROs. Descriptive statistics and ANCOVA models were used for analysis. At 36 months, GBR resulted in a mean RDF of 2.13 ± 1.26 mm, compared to 1.64 ± 1.54 mm with OFD (p = .18). No significant differences were found in PPD, BOP, SUP, REC, or PROs between the groups. Treatment success (defined as no additional bone loss, PPD ≤ 5 mm, no BOP, and no SUP) was achieved in 46.2% of GBR cases and 20% of OFD cases (p = 0.053). GBR provided improved short-term defect fill and higher treatment success compared to OFD, although the differences were not statistically significant. Both procedures maintained clinical parameters over 36 months, with similar patient satisfaction (PROs) observed for GBR and OFD. The adjunct use of DBBM and NBCM may offer clinical benefits for peri-implantitis cases with specific bony defect morphology.