Background. Due to its antioxidant, anti-inflammatory, anti-apoptosis, and anti-fatigue properties, molecular hydrogen (H2) is potentially a novel therapeutic nutrient for patients with coronavirus acute disease 2019 (COVID-19). We determined the efficacy and safety profile of hydrogen-rich water (HRW) to reduce the risk of COVID-19 progression. Methods: We also conducted a phase 3, triple-blind, randomised, placebo-controlled trial to evaluate treatment with HRW initiated within 5 days after the onset of signs or symptoms in primary care patients with mild-to-moderate, laboratory-confirmed COVID-19. Participants were randomised to receive HRW or placebo twice daily for 21 days. The incidence of clinical worsening and adverse events were the primary endpoints. Results: A total of 675 participants were followed up to day 30. HRW was not superior to placebo in preventing clinical worsening at day 14: in H2 group, 46.1% in the H2 group, 43.5% in the placebo group, hazard ratio 1.09, 90% confidence interval [0.90–1.31]. One death was reported at day 30 in the H2 group and two in the placebo group at day 30. Adverse events were reported in 91 (27%) and 89 (26.2%) participants, respectively. Conclusions: HRW taken twice daily from the onset of COVID-19 symptoms for 21 days did not reduce clinical worsening.