Abstract: nutrients Article Temporal Association of Reduced Serum Vitamin D with COVID-19 Infection: Two Single-Institution Case–Control Studies Diviya Gupta † , Sahit Menon † , Michael H. Criqui and Bryan K. Sun * School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; digupta@health.ucsd.edu (D.G.); s1menon@health.ucsd.edu (S.M.); mcriqui@health.ucsd.edu (M.H.C.) * Correspondence: bryansun@health.ucsd.edu; Tel.: +1-(858)-534-9418 † These authors contributed equally to this work. Citation: Gupta, D.; Menon, S.; Criqui, M.H.; Sun, B.K. Temporal Association of Reduced Serum Vitamin D with COVID-19 Infection: Two Single-Institution Case–Control Studies. Nutrients 2022, Abstract: (1) Background: Vitamin D supplementation has been proposed for the prevention and treatment of COVID-19, but it is not clear if reduced serum vitamin D predisposes individuals to COVID-19 and/or is a secondary consequence of infection. This study assessed the temporal association between serum vitamin D and COVID-19 with two single-institution case–control studies through the University of California San Diego (UCSD) Health System. (2) Methods: This study included patients who tested positive for COVID-19 from 1 January to 30 September 2020 with serum 25-hydroxy-vitamin D (25(OH)D) measured within 180 days of diagnosis. Patients were separated based on whether 25(OH)D was measured before (n = 107 cases, 214 controls) or after (n = 203 cases, 406 controls) COVID-19 diagnosis. COVID-19 infection status was the outcome variable in the pre-diagnosis study, whereas serum 25(OH)D level was the outcome variable in the post-diagnosis study. (3) Results: Serum 25(OH)D levels were not associated with the odds of subsequent COVID-19 infection (OR 1.0, 95% CI: 1.0 to 1.0, p = 0.98). However, COVID-19-positive individuals had serum 25(OH)D measurements that were 2.7 ng/mL lower than the controls (95% CI: −5.2 to −0.2, p = 0.03). (4) Conclusions: In our study population, serum 25(OH)D levels were not associated with the risk of acquiring COVID-19 infection but were reduced in subjects after COVID-19 infection. These results support the possibility that reduced serum 25(OH)D is a consequence and not a cause of COVID-19 infection. 14, 2757. https://doi.org/10.3390/ nu14132757 Keywords: COVID-19; vitamin D; 25(OH)D; case–control study Academic Editors: William B. Grant and Ronan Lordan Received: 19 June 2022 Accepted: 28 June 2022 Published: 2 July 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 Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).