BACKGROUND Aggressive familial giant-cell granulomas of the jaws can be severely deforming. Surgical and nonsurgical treatments may be associated with multiple recurrences. Denosumab, a new generation antiresorptive drug, is an osteoclast inhibitor, which may be particularly useful to manage such potentially disfiguring lesions. METHODS Two sisters, both with a history of multiple recurrent aggressive central giant-cell granuloma (CGCG)-like lesions in both jaws, were referred for management. All lesions were histologically consistent with the diagnosis of CGCG. The lesions were treated surgically with curettage and perilesional injection of triamcinolone. In particular, the older sister had four separate anatomic sites where some of her lesions had multiple recurrences necessitating three repeat procedures. A course of subcutaneous denosumab was administered following the last giant-cell granuloma removal in both sisters. RESULTS Bony healing was normal. No further recurrences were observed over 3.5 years of follow-up after denosumab therapy in either sister. CONCLUSIONS In this small cohort comprising two sisters with multiple aggressive recurrent giant-cell granuloma lesions at multiple sites in the mouth, subcutaneous denosumab administration was associated with success over 3.5 years of follow-up. This report cautiously adds to the clinical experience in the use of denosumab for the treatment of recurrent aggressive familial CGCG lesions.