We developed an effective regenerative therapy, referred to as platelet-derived growth factor-BB (PDGF-BB)-modulated guided tissue regenerative (GTR) therapy (P-GTR), capable of achieving periodontal regeneration of horizontal (Class III) furcation defects in the beagle dog. To determine its efficacy, repair and regeneration of horizontal furcation defects by P-GTR therapy and GTR therapy were compared. Chronically inflamed horizontal furcation defects were created around the second (P2) and fourth mandibular premolars (P4). After demineralization of the root surfaces with citric acid, the surfaces of left P2 and P4 were treated with PDGF-BB (P-GTR therapy) and those of contralateral teeth were treated with vehicle only (GTR therapy). Periodontal membranes were placed and retained 0.5 mm above the cemento-enamel junction for both groups. The mucoperiosteal flap was sutured in a coronal position and plaque control was achieved by daily irrigation with 2% chlorhexidine gluconate. At 5, 8, and 11 weeks, two animals each were sacrificed by perfusion with 2.5% glutaraldehyde through the carotid arteries, and the lesions were sliced mesio-distally, demineralized, dehydrated, and embedded. Periodontal healing and regeneration after GTR and P-GTR therapy were compared by histomorphometric as well as morphological analysis. Morphometric analysis for each time period was performed on the pooled samples of P2 and P4. Five weeks after both therapies, the lesions were filled primarily by tissue-free area, epithelium, inflamed tissue, and a small amount of newly formed fibrous connective tissue. At 8 and 11 weeks after P-GTR therapy, there was a statistically greater amount of bone and periodontal ligament formed in the lesions. The newly formed bone filled 80% of the lesion at 8 weeks and 87% at 11 weeks with P-GTR therapy, compared to 14% of the lesion at 8 weeks and 60% at 11 weeks with GTR therapy. Also, with P-GTR therapy there was less epithelium and tissue-free area, less inflamed tissue, and less connective tissue. Morphological analysis indicated that the defects around P2 revealed faster periodontal repair and regeneration than those around P4. While the lesions around P2 were effectively regenerated by 11 weeks even after GTR therapy, those around P4 failed to regenerate. On the other hand, P-GTR therapy further promoted periodontal repair and regeneration so that at 8 weeks the lesions around P2 and P4 demonstrated complete and nearly complete regeneration, respectively. Interestingly, P-GTR therapy stimulated formation of fibrous connective tissue compared to GTR therapy in the early stages of repair, thereby filling the wound space with the tissue and stabilizing the wound. Later, the fibrous connective tissue was found to be mineralized into bone or cementum depending on locations during remodeling. Consequently, P-GTR therapy effectively promoted periodontal regeneration with reproducibility.