Abstract: pharmaceuticals Systematic Review Protective Effect of Vitamin D Supplementation on COVID-19-Related Intensive Care Hospitalization and Mortality: Definitive Evidence from Meta-Analysis and Trial Sequential Analysis Christiano Argano 1, * , Raffaella Mallaci Bocchio 1 , Giuseppe Natoli 1 , Salvatore Scibetta 1 , Marika Lo Monaco 1,2 and Salvatore Corrao 1,2 1 2 * Citation: Argano, C.; Mallaci Bocchio, R.; Natoli, G.; Scibetta, S.; Lo Monaco, M.; Corrao, S. Protective Effect of Vitamin D Supplementation on COVID-19-Related Intensive Care Hospitalization and Mortality: Definitive Evidence from Meta-Analysis and Trial Sequential Analysis. Pharmaceuticals 2023, 16, 130. https://doi.org/10.3390/ ph16010130 Academic Editor: Julia O. Fedotova Internal Medicine Department iGR, National Relevance Hospital Trust, ARNAS Civico, Di Cristina e Benfratelli, 90127 Palermo, Italy Dipartimento di Promozione della Salute, Materno Infantile, Medicina Interna e Specialistica di Eccellenza “G. D’Alessandro”, PROMISE, University of Palermo, 90127 Palermo, Italy Correspondence: chargano@yahoo.it; Tel.: +39-091-655-2065; Fax: +39-091-666-3167 Abstract: Background: The COVID-19 pandemic represents one of the world’s most important challenges for global public healthcare. Various studies have found an association between severe vitamin D deficiency and COVID-19-related outcomes. Vitamin D plays a crucial role in immune function and inflammation. Recent data have suggested a protective role of vitamin D in COVID-19related health outcomes. The purpose of this meta-analysis and trial sequential analysis (TSA) was to better explain the strength of the association between the protective role of vitamin D supplementation and the risk of mortality and admission to intensive care units (ICUs) in patients with COVID-19. Methods: We searched four databases on 20 September 2022. Two reviewers screened the randomized clinical trials (RCTs) and assessed the risk of bias, independently and in duplicate. The pre-specified outcomes of interest were mortality and ICU admission. Results: We identified 78 bibliographic citations. After the reviewers’ screening, only five RCTs were found to be suitable for our analysis. We performed meta-analyses and then TSAs. Vitamin D administration results in a decreased risk of death and ICU admission (standardized mean difference (95% CI): 0.49 (0.34–0.72) and 0.28 (0.20–0.39), respectively). The TSA of the protective role of vitamin D and ICU admission showed that, since the pooling of the studies reached a definite sample size, the positive association is conclusive. The TSA of the protective role of vitamin D in mortality risk showed that the z-curve was inside the alpha boundaries, indicating that the positive results need further studies. Discussion: The results of the meta-analyses and respective TSAs suggest a definitive association between the protective role of vitamin D and ICU hospitalization. Keywords: vitamin D; COVID-19; ICU hospitalization; mortality; meta-analysis; trial sequential analysis Received: 23 November 2022 Revised: 27 December 2022 Accepted: 31 December 2022 Published: 16 January 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).