This case series investigated the effect of a combination therapy utilizing connective tissue graft (CTG) in the treatment of periodontal regeneration of mandibular Class III/IV furcation involvement (FI). Six patients diagnosed with periodontitis stage III or IV (grade A to C), presenting with Class III or IV FI, were treated with fibroblast growth factor-2 and carbonate apatite in combination with CTG. The following clinical parameters were evaluated at baseline and after 6, 12, and 18 months: periodontal probing depth, clinical attachment level, furcation invasion, radiographic vertical defect depth, and gingival phenotype. Significant improvements in clinical parameters were observed in all treated FI sites. Four Class III defects and one Class IV defect obtained complete closure, and one Class IV defect was improved to Class I. This case series showed the potential of administering combination regenerative therapy for changing the prognosis of hopeless teeth with severe furcation defects.