Giant cell lesions of bone share similar clinical, radiological, and histological features. The most challenging differential diagnosis is between giant cell tumor (GCT) and brown tumor (BT) secondary to hyperparathyroidism. Differential diagnosis is based on determining serum calcium concentration and other markers of calcium metabolism. The authors present the unusual case of a 37-year-old Caucasian woman affected by a GCT of the proximal left tibia and concomitant asymptomatic primary hyperparathyroidism (PHPT) due to a parathyroid adenoma. The presence of two concurrent diseases complicated diagnosis and relative treatment. The patient was first treated for the adenoma, then after 9 months, she underwent curettage of tibial GCT. Denosumab treatment was administered for 12 months to control a relapse occurring at 15 months post-curettage. At 32-month follow-up from primary tibial surgery, the patient was free from tumor disease. To our knowledge, this is the first case in the literature reporting the concomitant presence of asymptomatic PHPT and GCT. The possibility of concomitant finding these two diseases has to be considered during the decision-making process.