Coronavirus disease 2019 (COVID-19) is currently the major public health problem worldwide. Neutral electrolyzed saline solution that contains reactive chlorine and oxygen species may be an effective therapeutic. In the present study, the treatment efficacy of intravenous and/or nebulized neutral electrolyzed saline combined with usual medical care vs. usual medical care alone was evaluated in ambulatory patients with COVID-19. A prospective, 2-arm, parallel-group, randomized, open-label, multi-center, phase I-II clinical trial including 214 patients was performed. The following two outcomes were evaluated during the 20-day follow-up: i) The number of patients with disease progression; and ii) the patient acceptable symptom state. Serial severe acute respiratory syndrome coronavirus 2 naso/oro-pharyngeal detection by reverse transcription-quantitative (RT-q) PCR was performed in certain patients of the experimental group. Biochemical and hematologic parameters, as well as adverse effects, were also evaluated in the experimental group. The experimental treatment decreased the risk of hospitalization by 89% [adjusted relative risk (RR)=0.11, 95% confidence interval (CI): 0.03-0.37, P