Background: Fatigue is a common presenting symptom in primary hyperparathyroidism (PHPT). Although fatigue alone is not currently an indication for parathyroidectomy, it can have a significant detrimental effect on quality of life. The purpose of this study was to determine if there are underlying differences in demographic or disease characteristics in patients with PHPT who present with fatigue compared with those who do not. Methods: We reviewed a prospective database of 2197 patients undergoing parathyroidectomy for PHPT by three endocrine surgeons from 2001 to 2019. Patients were divided into two groups based on the presence or absence of fatigue as a presenting symptom. Objective measures of disease severity were then compared between groups. Results: A total of 1379 (63%) patients presented with fatigue. Patients presenting with fatigue were more likely to be female and to have a prior fracture, lower preoperative serum calcium (Ca), and normocalcemic PHPT. There were no statistically significant differences between groups in age, body mass index, history of nephrolithiasis, or preoperative serum parathyroid hormone levels. Patients presenting with fatigue were also more likely to have smaller parathyroid glands and multiglandular disease. No statistically significant differences were detected in postoperative serum Ca and parathyroid hormone levels, or cure or recurrence rates. Conclusions: Patients with PHPT who report fatigue as a presenting symptom present with more complex disease as manifested by a higher incidence of multiglandular disease and normocalcemic PHPT. Despite this, surgical cure is equivalent to other patients. Therefore, fatigue should be a discrete indication for parathyroidectomy in PHPT.