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Background Zinc supplementation has been considered a potential therapy for coronavirus disease 2019 (COVID-19). We aimed to examine zinc efficacy in adult patients with COVID-19 infection. Methods We conducted a prospective, randomized, double-blind, placebo-controlled multicenter trial. Patients who were tested positive for COVID-19 without end-organ failure were randomized to oral zinc (n = 231) or matching placebo (n = 239) for 15 days. The primary combined outcome was death due to COVID-19 or intensive care unit (ICU) admission ≤30 days after randomization. Secondary outcomes included length of hospital stay for inpatients and duration of COVID-19 symptoms with COVID-19–related hospitalization for outpatients. Results 190 patients (40.4%) were ambulatory and 280 patients (59.6%) were hospitalized. Mortality at 30 days was 6.5% in the zinc group and 9.2% in the placebo group (OR: .68; 95% CI .34–1.35); ICU admission rates were, respectively, 5.2% and 11.3% (OR: .43; 95% CI .21–.87). Combined outcome was lower in the zinc group versus the placebo group (OR: .58; 95% CI .33–.99). Consistent results were observed in prespecified subgroups of patients aged Conclusions Our results showed that, in COVID-19 patients, oral zinc can decrease 30-day death, ICU admission rate and can shorten symptom duration. Clinical Trials Registration. ClinicalTrials.gov, NCT05212480.