The purpose of this study was to compare Bio-Oss (BO), an anorganic bovine bone xenograft, in combination with Bio-Gide (BG), a bioabsorbable collagen barrier, to open-flap debridement (OFD) surgery in human mandibular Class II furcation defects. A total of 31 furcations (18 treatment, 13 control) in 21 patients were treated. There was a statistically significant improvement in most clinical indices for the BO/BG group, with minimal improvement noted for the OFD group. Vertical probing depth reduction of 2.0 mm and horizontal probing depth reduction of 2.2 mm were noted for the BO/BG group, with 0.3 mm and 0.2 mm reductions, respectively, noted for OFD. Hard tissue measurements showed 2.0 mm of vertical furcation bone fill for BO/BG and 0.5 mm for OFD. The BO/BG group had 3.0 mm of horizontal furcation bone fill, and the OFD group had 0.9 mm. The BO/BG group had a defect resolution of 82.7%; 42.5% was noted for the OFD group. There was a statistically significant difference between BO/BG and OFD in all soft and hard tissue measurements with the exception of attachment level, recession, and alveolar crest resorption.