Primary hyperparathyroidism (pHPT) is a prevalent disorder of dysregulated calcium homeostasis, marked by excessive secretion of parathyroid hormone (PTH), which results in alterated calcemia and renal and/or skeletal complications. Most patients are diagnosed before experiencing overt clinical symptoms, often as a result of blood tests performed for other disorders. When symptoms do manifest, they are associated with dysfunction of the parathyroid glands. Surgical treatment is considered the first choice and the only curative treatment for pHPT, offering advantages for both symptomatic and asymptomatic patients. The aim of this study is to report our experience in the management of 6 selected complex cases, which often require a multidisciplinary approach due to the lack of established diagnostic and therapeutic algorithms and the variability of clinical presentation and atypical parathyroid adenoma location. We present a series of cases examining the various treatment approaches in six distinct patients: one patient with parathyroid carcinoma with concomitant parathyroid adenoma, a case involving mediastinal parathyroidectomy, a case with an intrathymic parathyroid adenoma, two cases of recurrent pHPT, and one case of hereditary pHPT in Multiple Endocrine Neoplasia (MEN) 1 syndrome. The combination of parathyroid ultrasound and Tc-99m sestamibi scintigraphy is effective for localizing parathyroid adenomas in most patients. Additional imaging, such as single photon emission computed tomography/computed tomography (SPECT/CT) or 18F-Fluorocholine positron emission tomography/computed tomography (18F-FCH PET/CT), may be necessary in other cases. Intraoperative parathyroid hormone monitoring is valuable for detecting double adenomas in patients affected by hereditary familial hyperparathyroidism from MEN 1. Several studies highlight that the surgeon's expertise is the most critical determinant of a safe and successful surgical outcome.