Abstract At present, no agents are known to be effective in preventing Covid-19. Based on current knowledge of the pathogenesis of this disease, we suggest that SARS-CoV-2 infection might be attenuated by directly maintaining innate pulmonary redox, metabolic and dilation functions using well-tolerated medications that are known to serve these functions, specifically, using a low dose aerosolized combination of glutathione, inosine and potassium. From June 1 to July 10, 2020, we conducted a low-intervention open-label single-centre study to evaluate safety and efficacy of pre-exposure prophylaxis (PrEP) with the aerosolized combination medications (ACM) on SARS-CoV-2 incidence in 99 healthcare workers (HCWs) at a hospital that was designated to treat Covid-19 patients. We also retrospectively compared SARS-CoV-2 incidence in the ACM users to that in 268 untreated HCWs at the same hospital. Eligible participants received an aerosolized combination of 21.3 mg/ml glutathione, 8.7 mg/ml inosine in 107 mM potassium solution for 14 days. The main outcome was the frequency of laboratory confirmed SARS-CoV-2 cases, defined as individuals with positive genetic or immunological tests within 28 days of the study period. During the PrEP period, solicited adverse events occurred in five participants; all were mild and transient reactions. SARS-CoV-2 was detected in 2 ACM users (2%, 95% CI: 0.3% to 7.1%), which was significantly less than the incidence in 24 nonusers (9%, 95% CI: 5.8% to 13.0%; P = 0.02). Our findings might be used either to prevent SARS-CoV-2 infection, or to support ongoing and new research into more effective treatments for Covid-19. The study was registered with rosrid.ru, AAAA-A20-120061690058-2, and isrctn.com, ISRCTN34160010.