Background: Although significant clinical improvements were reported with the regeneration of periodontal infrabony defects (PID), graft stability of particulate bone substitutes remains an issue. Aim: Evaluate the efficacy of a combination of synthetic bone substitute with binding capacities (biphasic calcium sulphate (BB)) and a xenograft versus open flap debridment (OFD), through a minimally invasive surgical technique (MIST), for the treatment of PID. Material & Methods: A pragmatic, randomized controlled clinical trial of parallel design was performed. Twenty patients treated with MIST approach, providing one defect site with an infrabony component of at least 4mm deep and 2mm wide, were randomly allocated either to grafting with a combination of BB+xenograft (test group) or OFD (control group). At baseline and 12 months post-surgery, blind examiners assessed periodontal clinical parameters and marginal radiographic bone levels. Occurrence of complications and patient's satisfaction with treatment and aesthetics were also evaluated. Results: Both groups showed significant improvements in clinical parameters after 12 months. Intergroup comparison evidenced a tendency for better outcomes for the test group vs control group, regarding average PPD reduction (4.0±1.25mm vs 3.1±1.37mm) and CAL gain (3.3±1.06mm vs 2.4±1.06mm), despite not reaching significant statistically differences. Conclusion: Despite, not showing significant differences, it is suggested that in more challenging defects, as for non-contained morphology, the combination of MIST approach with BB+xenograft can have a beneficial added effect in terms of improving PPD reduction and CAL gain. Clinical implications: MIST+BB+xenograft appears to positively potentiate IPD's treatment. Schlagwörter: periodontal, infrabony defect, minimally invasive surgery, regeneration