Background <p>Periodontal intrabony defects pose significant challenges in periodontal therapy. Traditional surgical approaches often lead to substantial morbidity and high costs. Recently, endoscopic-assisted subgingival debridement (EASD) has emerged as a non-inferior alternative. This study aims to establish the efficacy of the endoscopic-assisted flapless approach to periodontal regeneration compared to periodontal regeneration with the papilla preservation technique (PPT) in managing residual periodontal intrabony defects.</p> Methods <p>This single-centre single-blinded randomized controlled clinical trial aims to recruit 56 participants with residual periodontal intrabony defects. Subjects will be randomly assigned to receive either EASD combined with enamel matrix derivatives (EMD) (test therapy) or PPT combined with EMD (control therapy) in a 1-to-1 ratio, delivered by the clinical investigator. Subjects will be followed up to 12&#xa0;months post-operation, and an independent, blinded assessor will be responsible for collecting clinical, radiographic endpoints, and patient-reported outcomes measures.</p> Discussion <p>This study aims to produce information on the efficacy of periodontal regeneration with EMD in combination with EASD or PPT in the management of intrabony periodontal defects. The findings of this study will assess whether the endoscopic-assisted flapless approach is a non-inferior alternative to the PPT approach for periodontal regeneration, offering additional benefits in terms of patient morbidity and operative time.</p> Trial registration <p>ClinicalTrials.gov NCT06978036.</p>