Background: Both the anti-infective and anti-inflammatory properties of vitamin D, an essential hormone of calcium homeostasis, have ample support in the literature. The high rates of vitamin D deficiency among patients with chronic hepatitis C are also well known. That supplementation with vitamin D may boost sustained viral response rates in vitamin D deficient, hepatitis C virus (HCV) infected patients undergoing Interferon-alpha (IFN) treatment, on the other hand, is controversial. Surprisingly, studies considering in this latter setting what are the effects of IFN treatment (with or without vitamin D supplementation) on the other major regulator of mineral metabolism, i.e. the Parathyroid hormone (PTH), are lacking. Aim: Evaluate the impact of interferon-based treatment against HCV (±cholecalciferol supplementation) on vitamin D and PTH homeostasis. Methods: A series of 40 consecutive patients received pegylated IFN plus ribavirin to treat chronic hepatitis C. At the discretion of their physician, some of them (N. = 27) received vitamin D supplementation while others did not (N. = 13). All had measured plasma 25-hydroxycholecalciferol and PTH concentrations at baseline, at completion of the 4th (TW4) and 12th treatment week (TW12) and at 24 weeks after the end of therapy (SVR24). Results: Plasma PTH concentration increased significantly from baseline during treatment, raising to 44.8 [30.7-57.2] pg/mL at TW4 (p=0.01), 47.0 [37.1-63.2] pg/mL at TW12 (p=0.006) to return to baseline levels in the follow-up (34.5 [27.6-43.0]; p=0.16). The proportion of patients who satisfied criteria for hyperparathyroidism was higher at TW12 (N=10, 25%) than at TW4 (N=6, 15%). There was no statistical correlation between vitamin D and PTH blood levels (ρ=-0.07; p=0.65). Conclusion: An increase in plasma PTH occurs systematically during IFN treatment of HCV patients and cannot be prevented by vitamin D supplementation.