Abstract: nutrients Article Positive Effects of Vitamin D Supplementation in Patients Hospitalized for COVID-19: A Randomized, Double-Blind, Placebo-Controlled Trial Sophie De Niet 1, * , Mickaël Trémège 1 , Monte Coffiner 1 , Anne-Francoise Rousseau 2 , Doriane Calmes 3 , Anne-Noelle Frix 3 , Fanny Gester 3 , Muriel Delvaux 3 , Anne-Francoise Dive 3 , Elora Guglielmi 3 , Monique Henket 3 , Alicia Staderoli 3 , Didier Maesen 4 , Renaud Louis 3 , Julien Guiot 3 and Etienne Cavalier 5 1 2 3 4 5 * Citation: De Niet, S.; Trémège, M.; Coffiner, M.; Rousseau, A.-F.; Calmes, D.; Frix, A.-N.; Gester, F.; Delvaux, M.; Dive, A.-F.; Guglielmi, E.; et al. Positive Effects of Vitamin D Supplementation in Patients Hospitalized for COVID-19: A Randomized, Double-Blind, Placebo-Controlled Trial. Nutrients 2022, 14, 3048. https://doi.org/ 10.3390/nu14153048 Academic Editor: Connie Weaver Received: 8 June 2022 Accepted: 19 July 2022 Published: 26 July 2022 Clinical Department, Laboratoires SMB SA, 1080 Brussels, Belgium; mtrem@smb.be (M.T.); mcoff@smb.be (M.C.) Department of Intensive Care, University of Liège, CHU Sart-Tilman, 4000 Liège, Belgium; afrouseau@chuliege.be Department of Pneumology and Allergology, University of Liège, CHU Sart-Tilman, 4000 Liège, Belgium; d.calmes@chuliege.be (D.C.); affrix@chuliege.be (A.-N.F.); f.gester@chuliege.be (F.G.); muriel.delvaux@chuliege.be (M.D.); af.dive@chuliege.be (A.-F.D.); elora.guglielmi@chuliege.be (E.G.); monique.henket@chuliege.be (M.H.); alicia.staderoli@chuliege.be (A.S.); renaud.louis@chuliege.be (R.L.); j.guiot@chuliege.be (J.G.) Department of Hospital Pharmacy, CHU Sart-Tilman, 4000 Liège, Belgium; dmaesen@chuliege.be Department of Clinical Chemistry, University of Liège, CIRM, CHU Sart-Tilman, 4000 Liège, Belgium; etienne.cavalier@chu.ulg.ac.be Correspondence: sdeni@smb.be; Tel.: +32-2-411-4828 Abstract: Retrospective studies showed a relationship between vitamin D status and COVID-19 severity and mortality, with an inverse relation between SARS-CoV-2 positivity and circulating calcifediol levels. The objective of this pilot study was to investigate the effect of vitamin D supplementation on the length of hospital stay and clinical improvement in patients with vitamin D deficiency hospitalized with COVID-19. The study was randomized, double blind and placebo controlled. A total of 50 subjects were enrolled and received, in addition to the best available COVID therapy, either vitamin D (25,000 IU per day over 4 consecutive days, followed by 25,000 IU per week up to 6 weeks) or placebo. The length of hospital stay decreased significantly in the vitamin D group compared to the placebo group (4 days vs. 8 days; p = 0.003). At Day 7, a significantly lower percentage of patients were still hospitalized in the vitamin D group compared to the placebo group (19% vs. 54%; p = 0.0161), and none of the patients treated with vitamin D were hospitalized after 21 days compared to 14% of the patients treated with placebo. Vitamin D significantly reduced the duration of supplemental oxygen among the patients who needed it (4 days vs. 7 days in the placebo group; p = 0.012) and significantly improved the clinical recovery of the patients, as assessed by the WHO scale (p = 0.0048). In conclusion, this study demonstrated that the clinical outcome of COVID-19 patients requiring hospitalization was improved by administration of vitamin D. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims..