Objective: To evaluate a comparison of open-flap debridement (OFD) with or without the use of enamel matrix proteins (EMP) for the treatment of infrabony defects. Method and Materials: Ten volunteers (38 infrabony defects) were randomized to receive OFD + EMP (test site) and OFD (control site). Clinical outcomes included mean changes in Plaque Index, Gingival Index, probing pocket depth (PPD), relative attachment level (RAL), gingival recession, width of keratinized tissue, and dental mobility at baseline and at 24 months. Results: A significant reduction of 4.21 ± 0.97 mm was observed in PPD for the OFD + EMP group (from 6.30 ± 0.99 mm to 2.09 ± 0.97 mm) and of 3.28 ± 1.23 mm for the OFD group (from 6.13 ± 0.88 mm to 2.85 ± 1.42 mm) (P .001). The reduction in PPD was statistically significantly greater for OFD + EMP compared to OFD (P = .03). The mean RAL decreased from 13.26 ± 1.88 mm to 7.57 ± 2.05 mm for the OFD + EMP group (a gain of 5.69 ± 1.96 mm) and from 13.37 ± 1.71 mm to 8.13 ± 1.34 mm (P .001) for the OFD group (a gain of 5.24 ± 1.55 mm). Gingival recession was higher in the OFD + EMP group than in the OFD group. The mean keratinized tissue significantly decreased from 4.41 ± 1.39 mm to 3.63 ± 1.54 mm for OFD flap group (P .01). Conclusion: Both treatment modalities were efficient in improving RAL and PPD. Within groups, there was a significant reduction in keratinized tissue for OFD and a significant postoperative recession for the OFD + EMP group. Infrabony defects treated with OFD + EMP showed significantly more PPD reduction when compared to OFD. Keywords: enamel matrix proteins, infrabony defects, periodontal diseases, periodontal therapy, randomized clinical trials, regenerative periodontal therapy