This human clinical trial evaluated the clinical and histologic response to recombinant human platelet-derived growth factor-BB (rhPDGF-BB) delivered in bone allograft for the treatment of advanced Class II furcation defects. Three mandibular and one maxillary molar furcation defects were treated: Two received 0.5 mg/mL and two received 1.0 mg/mL rhPDGF-BB, in all cases mixed with DFDBA. Clinical probing depths and attachment levels were obtained presurgically and 9 months postsurgical, after which the teeth and surrounding tissues were removed en bloc. Both concentrations of rhPDGF-BB resulted in substantially improved horizontal (mean 3.5 mm) and vertical (mean 4.25 mm) probing depths and attachment levels (mean 3.75 mm). Histologic evaluation revealed periodontal regeneration, including new bone, cementum, and periodontal ligament coronal to the reference notch. Regeneration was also present coronal to the original osseous crest. In one case where an enamel projection extended into the fornix of the furcation, new calcified tissue with new inserting connective tissue fibers was observed over the enamel. This study documented the favorable tissue response to rhPDGF-BB treatment at both the clinical and microscopic levels, provided the first human histologic evidence that new calcified tissue with inserting collagen fibers can occur over enamel projections within furcations, and demonstrated for the first time that complete periodontal regeneration can be achieved in advanced Class II furcation defects using a combination of purified recombinant growth factor and bone allograft.