Abstract: Biological Trace Element Research (2021) 199:3642–3646 https://doi.org/10.1007/s12011-020-02512-1 Do Zinc Supplements Enhance the Clinical Efficacy of Hydroxychloroquine?: a Randomized, Multicenter Trial Sherief Abd-Elsalam 1 & Shaimaa Soliman 2 & Eslam Saber Esmail 1 & Mai Khalaf 1 & Ehab F. Mostafa 3 & Mohammed A. Medhat 3 & Ossama Ashraf Ahmed 4 & Mohamed Samir Abd El Ghafar 5 & Mohamed Alboraie 6 & Sahar M. Hassany 3 Received: 1 September 2020 / Accepted: 23 November 2020 / Published online: 27 November 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract No specific treatment for COVID-19 infection is available up till now, and there is a great urge for effective treatment to reduce morbidity and mortality during this pandemic. We aimed to evaluate the effect of combining chloroquine/hydroxychloroquine (CQ/HCQ) and zinc in the treatment of COVID-19 patients. This was a randomized clinical trial conducted at three major University hospitals in Egypt. One hundred ninety-one patients with a confirmed diagnosis of COVID-19 infection were randomized into two groups: group I (96) patients received both HCQ and zinc, and group II (95) received HCQ only. The primary endpoints were the recovery within 28 days, the need for mechanical ventilation, and death. The two groups were matched for age and gender. They had no significant difference regarding any of the baseline laboratory parameters or clinical severity grading. Clinical recovery after 28 days was achieved by 79.2% in the zinc group and 77.9% in zinc-free treatment group, without any significant difference (p = 0.969). The need for mechanical ventilation and the overall mortality rates did not show any significant difference between the 2 groups either (p = 0.537 and 0.986, respectively). The age of the patient and the need for mechanical ventilation were the only risk factors associated with the patients’ mortality by the univariate regression analysis (p = 0.001 and < 0.001, respectively). Zinc supplements did not enhance the clinical efficacy of HCQ. More randomized studies are needed to evaluate the value of adding zinc to other therapies for COVID 19. ClinicalTrials.gov Identifier: NCT04447534 Keywords Zinc . Chloroquine . Antioxidants . COVID 19 . Treatment