The purpose of this study was to compare the effectiveness of three methods using calcium sulfate as a graft/barrier for the treatment of Class II mandibular furcation defects. Thirty-six defects in 17 patients were treated with a graft/barrier of pure calcium sulfate, calcium sulfate plus doxycycline, or demineralized freezedried bone allograft (DFDBA) in a 2:1 ratio by volume. Defects were randomly selected for treatment, and all measurement parameters were standardized to a light-cured acrylic resin stent at baseline and 6, 9, and 12 months. Linear regression, ANOVA, and chi-squared analysis revealed that all three groups showed significant bone fill (P .05), vertical and horizontal probing depth reduction, defect volume reduction, and a gain in vertical clinical attachment. Furthermore, the addition of either doxycycline or DFDBA to calcium sulfate significantly enhanced the clinical outcome more than did the calcium sulfate alone, and the addition of DFDBA was more effective in the treatment of Class II mandibular furcation defects than doxycycline.