Purpose: To evaluate the effectiveness of a bone substitute covered with a resorbable membrane versus open flap debridement for the treatment of periodontal infrabony defects. Materials and methods: Ninety-seven patients with one infrabony defect, which was 3 mm or deeper and at least 2 mm wide were randomly allocated either to grafting with a bone substitute covered with a resorbable barrier (BG group) or open flap debridement (OFD group) according to a parallel group design in five European centres. Blinded outcome measures assessed tooth loss, complications, patient's satisfaction with treatment and aesthetics, changes in probing attachment levels (PAL), probing pocket depths (PPD), gingival recessions (REC), radiographic bone levels (RAD) on standardised periapical radiographs, plaque index (PI) and marginal bleeding index (MBI). Results: 49 patients were randomly allocated to the BG group and 48 to the OFD group. At baseline there were more mobile teeth in the BG group (29 versus 15). One year after treatment two patients dropped out from the BG group and no teeth were lost. Three complications (minor postoperative wound dehiscence) occurred in the BG group versus none in the OFD group, where the difference was not statistically significant. The BG group obtained significantly greater statistical PAL gain (mean difference = -0.8 mm, 95%CI [-1.51; -0.03], P = 0.0428), PPD reduction (mean difference = -1.1 mm, 95%CI [-1.84; -0.19], P = 0.0165) and RAD gain (mean difference = -1.2 mm, 95%CI [-2.0; -0.4], P = 0.0058) compared to the OFD group. No statistically significant differences between the groups were observed for gingival recession, or the patient's satisfaction with the treatment and aesthetics. There were some statistically significant differences between the centres for PAL and PPD with the Italian centres reporting better outcomes. Conclusions: The use of a bone substitute covered with a resorbable membrane yielded significantly better statistical clinical outcomes than open flap debridement in the treatment of periodontal infrabony defects deeper than 3 mm, with regard to PAL gain, PPD reduction and RAD gain. Keywords: bone substitutes, infrabony defect, periodontitis, randomised controlled trial