Abstract: nutrients Article Effects of L -Arginine Plus Vitamin C Supplementation on Physical Performance, Endothelial Function, and Persistent Fatigue in Adults with Long COVID: A Single-Blind Randomized Controlled Trial Matteo Tosato 1 , Riccardo Calvani 1, * , Anna Picca 1,2 , Francesca Ciciarello 1 , Vincenzo Galluzzo 1 , Hélio José Coelho-Júnior 1,3 , Angela Di Giorgio 1 , Clara Di Mario 4 , Jacopo Gervasoni 1 , Elisa Gremese 1,3,4 , Paolo Maria Leone 1 , Antonio Nesci 1 , Anna Maria Paglionico 1 , Angelo Santoliquido 1,5 , Luca Santoro 1 , Lavinia Santucci 6 , Barbara Tolusso 4 , Andrea Urbani 1,7 , Federico Marini 8 , Emanuele Marzetti 1,3 and Francesco Landi 1,3 on behalf of the Gemelli against COVID-19 Post-Acute Care Team 1 2 3 4 5 6 Citation: Tosato, M.; Calvani, R.; Picca, A.; Ciciarello, F.; Galluzzo, V.; Coelho-Júnior, H.J.; Di Giorgio, A.; Di Mario, C.; Gervasoni, J.; Gremese, E.; et al. Effects of L -Arginine Plus Vitamin C Supplementation on Physical Performance, Endothelial Function, and Persistent Fatigue in Adults with Long COVID: A Single-Blind Randomized Controlled Trial. Nutrients 2022, 14, 4984. https://doi.org/10.3390/nu14234984 Academic Editors: Bruno Trimarco and Gaetano Santulli Received: 13 September 2022 Accepted: 20 November 2022 Published: 23 November 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2022 by the authors. 7 8 * Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy Department of Medicine and Surgery, LUM University, 70010 Casamassima, Italy Department of Geriatrics and Orthopedics, Università Cattolica del Sacro Cuore, 00168 Rome, Italy Immunology Core Facility, Gemelli Science Technological Park (GSTeP), Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy Department of Cardiovascular Sciences, Università Cattolica del Sacro Cuore, 00168 Rome, Italy Metabolomics Research Core Facility, Gemelli Science and Technology Park (GSTeP), Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy Department of Biochemistry and Clinical Biochemistry, Università Cattolica del Sacro Cuore, 00168 Rome, Italy Department of Chemistry, Sapienza University of Rome, 00185 Rome, Italy Correspondence: riccardo.calvani@policlinicogemelli.it; Tel.: +39-(06)-3015-5559 Abstract: Long COVID, a condition characterized by symptom and/or sign persistence following an acute COVID-19 episode, is associated with reduced physical performance and endothelial dysfunction. Supplementation of L -arginine may improve endothelial and muscle function by stimulating nitric oxide synthesis. A single-blind randomized, placebo-controlled trial was conducted in adults aged between 20 and 60 years with persistent fatigue attending a post-acute COVID-19 outpatient clinic. Participants were randomized 1:1 to receive twice-daily orally either a combination of 1.66 g L-arginine plus 500 mg liposomal vitamin C or a placebo for 28 days. The primary outcome was the distance walked on the 6 min walk test. Secondary outcomes were handgrip strength, flow-mediated dilation, and fatigue persistence. Fifty participants were randomized to receive either L -arginine plus vitamin C or a placebo. Forty-six participants (median (interquartile range) age 51 (14), 30 [65%] women), 23 per group, received the intervention to which they were allocated and completed the study. At 28 days, L-arginine plus vitamin C..