Background: In this study, we compare the effectiveness of enamel matrix derivative (EMD) associated with a simplified papilla preservation flap (SPPF) technique to SPPF alone when surgically treating supra-alveolar-type defects. Methods: Fifty patients, from 54 initially selected, presenting horizontal bone loss around 4 adjacent teeth, were treated by an SPPF technique; 25 participants also received EMD (test group) and 25 patients underwent flap surgery alone (control group). A complete clinical and radiographic examination was performed at baseline and 12 months after treatment. Pre- and post-therapy probing depth (PD), clinical attachment level (CAL), gingival recession (GR), and radiographic bone level (BL) were compared between treatments. Results: After 12 months, PD, CAL, and GR in both groups showed significant differences from baseline (P