Purpose: Interferon alpha (IFN-α) has been the mainstay of therapy for chronic hepatitis C. Side events of IFN-based therapy include autoimmune thyroiditis (10.7%). The effects of IFN gamma on calcium homeostasis have been well documented. Impacts of IFN-α on osteoclasts have been postulated. This study evaluated IFN-α induced autoimmune hyperparathyroidism, with or without eucalcemic state. Methods: 96 patients were evaluated, 45/90 patients treated with Pegylated IFN-α for chronic hepatitis C (group A- 75% alfa-2a, and 25% on alfa-2b), 36 patients with chronic hepatitis B (group B- 100% alfa-2a). 15 patients with multiple sclerosis (MS) (group C) treated with IFN beta for MS were recruited. Baseline and 24-week ionized calcium, serum parathyroid hormone intact (PTH intact), 24-hour urine calcium, bone densitometry, and parathyroid antibody (PTH-Ab) were measured in all subjects. Exclusion criteria: Parathyroid dysfunction, multiple endocrine neoplasia, hypercalcemic syndromes, hypervitaminosis D, renal failure, osteoporosis and sarcoidosis. Results: 23/96 patients (24%) had high normal serum calcium (>9.6 mg/dL). The 24-hour urine and total ionized calcium levels were elevated in 2/36 (5.6%) patients in Group B. Baseline serum PTH-intact and PTH Ab were normal in all groups. Group A, 9/45 patients (20%, alfa-2a 44%, 2b, 55%) in and Group-B, 6/36 patients (16.7%) developed elevated PTH levels and none in group C. PTH radionucleotide scan identified 1/36 (2.8%) patient with adenoma in group B. PTH Ab was found 9/45 (20%) in group A, 5/36 (13.9%) in group B, and none in Group C. Conclusion: Interferon alpha has autoimmune effects on parathyroid gland expressing elevated PTH level with PTH Ab without overt clinical manifestation of hyperparathyroidism. A larger sample size is required to confirm the potential effect of IFN alpha on calcium homeostasis, which might explain the symptoms of fatigue in chronic hepatitis C associated with IFN therapy.