Growth factors are considered an important component for periodontal wound healing and a key element in the periodontal regeneration triad. Randomized controlled clinical trials have demonstrated that purified recombinant human platelet-derived growth factor-BB (rhPDGF-BB) in combination with bone graft materials is effective in treating intrabony periodontal defects. Many clinicians are currently using rhPDGF-BB in combination with xenogeneic or allogeneic bone. Therefore, the purpose of this case series was to assess the clinical effectiveness of combining rhPDGF-BB with xenogeneic bone substitutes to treat severe intrabony periodontal defects. Three patients with challenging deep and wide intrabony defects were treated using a combination of rhPDGF-BB and xenogeneic graft matrix. Probing depth (PD) reduction, bleeding on probing (BOP), mobility reduction, and radiographic bone fill (RBF) were observed for 12 to 18 months. PD decreased from 9 mm to 4 mm, BOP was eliminated, mobility decreased, and RBF ranged from 85% to 95% over the postsurgical observation period. These results indicate that combination of rhPDGF-BB with xenogeneic bone substitutes is a safe and effective graft that leads to favorable clinical and radiographic outcomes for treating severe intrabony periodontal defects. Larger case series or randomized studies will further elucidate the clinical predictability of this treatment protocol. Int J Periodontics Restorative Dent 2023;43:193-200. doi: 1011607/prd.6313.