Abstract: nutrients Review Vitamin D Endocrine System and COVID-19: Treatment with Calcifediol Jose Manuel Quesada-Gomez 1,2, *, José Lopez-Miranda 1,3,4 , Marta Entrenas-Castillo 5 , Antonio Casado-Díaz 1,2,6 , Xavier Nogues y Solans 2,7 , José Luis Mansur 8 and Roger Bouillon 9, * 1 2 3 4 5 6 7 8 9 * Citation: Quesada-Gomez, J.M.; Lopez-Miranda, J.; Entrenas-Castillo, M.; Casado-Díaz, A.; Nogues y Solans, X.; Mansur, J.L.; Bouillon, R. Vitamin D Endocrine System and COVID-19: Treatment with Calcifediol. Nutrients 2022, 14, 2716. https://doi.org/10.3390/ nu14132716 Academic Editor: Federica I. Wolf Received: 22 April 2022 Accepted: 27 June 2022 Published: 29 June 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, 14004 Córdoba, Spain; md1lomij@uco.es (J.L.-M.); bb1cadia@uco.es (A.C.-D.) Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, 28029 Madrid, Spain; xnogues@psmar.cat Departamento de Medicina Interna, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain CIBER Fisiopatologia Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029 Madrid, Spain Hospital QuirónSalud, 14004 Córdoba, Spain; marenca@gmail.com Unidad de Gestión Clínica de Endocrinología y Nutrición, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain Internal Medicine Department, IMIM (Hospital del Mar Medical Research Institute), Hospital del Mar, 08003 Barcelona, Spain Centro de Endocrinología y Osteoporosis La Plata, Buenos Aires B1902ADQ, Argentina; joseluismansur@yahoo.com.ar Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, Catholic University of Leuven, 3000 Leuven, Belgium Correspondence: jmquesada@uco.es (J.M.Q.-G.); roger.bouillon@kuleuven.be (R.B.) Abstract: The COVID-19 pandemic is the greatest challenge facing modern medicine and public health systems. The viral evolution of SARS-CoV-2, with the emergence of new variants with in-creased infectious potential, is a cause for concern. In addition, vaccination coverage remains in-sufficient worldwide. Therefore, there is a need to develop new therapeutic options, and/or to optimize the repositioning of drugs approved for other indications for COVID-19. This may include the use of calcifediol, the prohormone of the vitamin D endocrine system (VDES) as it may have potential useful effects for the treatment of COVID-19. We review the aspects associating COVID-19 with VDES and the potential use of calcifediol in COVID-19. VDES/VDR stimulation may enhance innate antiviral effector mechanisms, facilitating the induction of antimicrobial peptides/autophagy, with a critical modulatory role in the subsequent host reactive hyperinflammatory phase during COVID-19: By decreasing the cytokine/chemokine storm, regulating the renin–angiotensin–bradykinin system (RAAS), modulating neutrophil activity and maintaining the integrity of the pulmonary epithelial barrier, stimulating epithelial repair, and directly and indirectly decreasing the increased coagulability and prothrombotic tendency associated with severe COVID-19 and its..