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AbstractBackgroundCentral giant cell granuloma (CGCG) is one of the most intriguing lesions of the jaws and its nature has not yet been fully elucidated. Clinically, some CGCG behave more aggressively, while others have an indolent course. In cases of aggressive CGCG of the maxilla, effective personalized therapies are worth understanding.Case reportWe report here a challenging case of aggressive CGCG in a 15‐year‐old girl which was misdiagnosed as an endodontic lesion. Radiographically, a large osteolytic lesion involving the hard palate from the central incisor to the second premolar, extending into the nasal cavity, with loss of the lamina dura and cortical resorption was observed. The lesion expanded aggressively after extensive curettage. With possible mutilation and defects due to a more radical approach to the lesion, treatment with systemic prednisone and intralesional triamcinolone hexacetonide associated with a calcitonin nasal spray was instituted. The decision in favor of this therapeutic strategy was made after careful immunohistochemical analysis of calcitonin and glucocorticoid receptors. The H‐score for the staining of glucocorticoid and calcitonin receptors in multinucleated giant cells was 222 and 153.6, respectively. The lesion reduced in size, and no adverse effects associated with medications were observed. Another curettage was performed, and only fibrous connective tissue was found. The patient is in follow‐up for 11 years without evidence of recurrence.ConclusionPharmacological agents hold clinical promise in cases of aggressive CGCG affecting the maxilla of pediatric patients. Investigating the expression of calcitonin and glucocorticoid receptors in order to plan treatment is very helpful in the decision to manage aggressive CGCG.