The differential diagnosis of primary hyperparathyroidism can be considered clinically, biologically and radiologically. Clinically, primary hyperparathyroidism should be suspected in case of diffuse pain, renal lithiasis, osteoporosis, repeated fracture, cognitive or psychiatric disorder, or disturbance of consciousness. Nevertheless, the differential diagnosis of primary hyperparathyroidism is mainly biological, particularly in atypical forms, which must be differentiated from hypercalcemia with hypocalciuria or non-elevated PTH on the one hand, and from normo-calcemia with elevated PTH, hypophosphatemia or hypercalciuria on the other. Any differential diagnosis must be preceded by an analysis of the factors likely to disturb phospho-calcium parameters: vitamin D deficiency (assay), renal insufficiency (eGFR measurement), malabsorption (inflammatory disease of the digestive tract, celiac disease, bariatric surgery, etc.), insufficient calcium intake (GRIO questionnaire) and iatrogenic causes (diuretics, anti-osteoporotic drugs, excessive vitamin D or calcium supplementation, lithium, corticosteroid therapy, phosphorus intake). Once these factors have been eliminated, hypercalcemia with hypocalciuria should suggest a genetic cause. Hypercalcemia with non-elevated PTH may be secondary to neoplasm, hypervitaminosis D (excessive intake, production or catabolism), immobilization or endocrine causes. Elevated PTH values without hypercalcemia must be differentiated from normo-calcemic hyperparathyroidism. High PTH levels are found in PTH-resistant patients, as well as in hypophosphatemic (especially X-linked) or hypercalciuric tubulopathies (certain rare diseases, immobilization, loop diuretics or idiopathic causes favored by a metabolic syndrome). Radiologically, brown tumor must be differentiated primarily from bone metastasis, chondrosarcoma and giant cell tumor.