The aim of this split-mouth clinical and radiographic study was to evaluate and compare the regenerative potential of a combination of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) and beta tricalcium phosphate (β-TCP) to the established technique of bone grafting with β-TCP alone in the surgical management of intraosseous defects. A total of 24 sites in 12 subjects with intraosseous defects were included and randomly divided into test (rhPDGF-BB + β-TCP) and control (β-TCP alone) sites. Clinical parameters were recorded at baseline, 3 months, and 6 months. Radiographic parameters were evaluated at baseline and 6 months. Both groups showed statistically significant reductions of all clinical parameters. Intergroup comparison demonstrated a significantly greater probing pocket depth reduction and clinical attachment level gain in the test group. The mean percentage defect fill was significantly greater in the test group than in the control group at 3 and 6 months, and greater improvement in defect angle was also evident in the test group. Although both groups showed definitive improvements in all parameters, the test group showed significantly better results when used to treat human periodontal intraosseous defects.