Astronauts are exposed to a wide variety of stressors ranging from radiation and microgravity to persistent fluids shifts, circadian shifts and the psychological stress of prolonged isolation and confinement. On deep space missions, beyond the range of the Earth's magnetosphere, ionizing radiation may increase oxidative stress and DNA damage, immune system dysregulation and alter the effectiveness of the cellular defense mechanisms. By reviewing the health problems reported by astronauts participated in previous space missions, it is evident that viral infections are not rare in space. Recent reports suggest that COVID-19 can last for a long time in communities. Although NASA implements countermeasures designed to limit crew illness during space missions such as a pre-flight quarantine, it is not clear whether an outbreak can be prevented. Currently, it is not likely that astronauts could get a viral infection, but the consequences of potential life-threatening viral diseases such as COVID-19 should be better characterized. In this paper we discuss why COVID-19 fatality in space might be significantly higher than on the Earth. The reasons for such an increased risk include 1) uselessness of social distancing due to microgravity 2) immune system dysregulation 3) possibly higher mutation rates of RNA viruses such as the novel coronavirus (SARS-CoV-2) 4) existence of strong selective pressure and 5) decreased maximum oxygen uptake. Given these considerations, the combined effects of microgravity, space radiation (and possibly other major space stressors) on the immune system of astronauts exposed to SARS-CoV-2 and possible interactions of the virus, space stressors and host should be carefully investigated.