Objective: To determine the efficacy of enamel matrix derivative (EMD) and forced eruption alone or in combination with freeze-dried bone allograft (FDBA) or demineralized FDBA (DFDBA) when managing infrabony defects. Method and Materials: Seventy-four patients with an inadequate biologic width due to subgingival caries were randomly assigned to one of three intervention groups: Ortho/EMD/FDBA (OEF) (n = 25), Ortho/EMD/DFDBA (OED) (n = 24), and Ortho/EMD alone without graft material as a control (OE) (n = 25). Each patient donated an infrabony defect. The primary outcomes were absolute change in probing depth (PD) reduction and clinical attachment level (CAL) gain from baseline to 1- and 3-year follow-up. Infrabony defects were surgically treated with EMD/FDBA, EMD/DFDBA, or EMD alone 4 weeks before orthodontic extrusive force was applied to reestablish a biologic width of 2 mm. Results: Seventy-four patients (OEF, n = 25; OED, n = 24; OE, n = 25) were analyzed. All groups demonstrated significant improvement in PD reduction and CAL gain from baseline. The changes at 1 year for PD were: OEF (mm, 95% CI), 4.3, 3.7 to 4.7; OED, 4.2, 3.6 to 4.9; and OE, 3.4, 3.1 to 3.7; for CAL, changes were: OEF, 4.3, 3.9 to 4.7; OED, 3.9, 3.5 to 4.4; and OE, 3.3, 3.1 to 3.5. Longer follow-ups showed similar findings. Conclusion: This study showed that both forced eruption/EMD/FDBA and forced eruption/EMD/DFDBA combination therapies result in greater soft tissue improvements at 1- and 3-year follow-up in addition to greater hard tissue improvements at 6-month re-entry compared with forced eruption/EMD alone. Keywords: bone, clinical trial, enamel matrix protein, forced eruption, randomized, tissue regeneration