This study evaluated the clinical, radiographic, and histologic response to Bio-Oss porous bone mineral when used alone or in combination with Bio-Gide bilayer collagen membrane in human periodontal defects. Four intrabony periodontal defects were treated: two received Bio-Oss alone and two were treated with a combination of Bio-Oss and Bio-Gide. Radiographs, clinical probing depths, and attachment levels were obtained preoperatively and 6 to 9 months postoperative, and teeth and surrounding tissues were biopsied. Both treatments significantly improved clinical probing depths and attachment levels, and the radiographic appearance suggested osseous fill. Histologic evaluation revealed that both treatments produced new cementum with inserting collagen fibers and new bone formation on the surface of the graft particles; this regenerative effect was more pronounced using the Bio-Oss/Bio-Gide combination, which resulted in 7 mm of new cementum and periodontal ligament and extensive new bone incorporating the graft. The membrane was intact at 7 months and partially degraded by 9 months after treatment. This human histologic study demonstrates that the prous bone mineral matrix used has the capacity to stimulate substantial new bone and cementum formation and that this capacity is further increased when the graft is used with a slowly resorbing collagen membrane.