Background Until now, no antiviral treatment has been proven to be effective for the coronavirus disease 2019 (COVID-19). The timing of oxygen therapy was considered to have a great influence on the symptomatic relief of hypoxemia and seeking medical intervention, especially in situations with insufficient medical resources, but the evidence on the timing of oxygen therapy is limited. Methods and findings Medical charts review was carried out to collect the data of hospitalized patients with COVID-19 infection confirmed in Tongji hospital, Wuhan from 30(th) December 2019 to 8(th) March 2020. In this study, the appropriate timing of oxygen therapy and risk factors associated with severe and fatal illness were identified and the effectiveness of antivirus on disease progression was assessed. Among 1362 patients, the prevalence of hypoxia symptoms was significantly higher in those patients with severe and fatal illness than in those with less severe disease. The onset of hypoxia symptoms was most common in the second to third week after symptom onset, and patients with critical and fatal illness experienced these symptoms earlier than those with mild and severe illness. In multivariable analyses, the risk of death increased significantly when oxygen therapy was started more than 2 days after hypoxia symptoms onset among critical patients (OR, 1.92; 95%CI, 1.20 to 3.10). Compared to the critically ill patients without IFN-a, the patients who were treated with IFN-a had a lower mortality (OR, 0.60; 95%CI, 0.39 to 0.91). Conclusions Early initiation of oxygen therapy was associated with lower mortality among critical patients. This study highlighted the importance of early oxygen therapy after the onset of hypoxia symptoms. Our results also lend support to potentially beneficial effects of IFN alpha on critical illness. Author summary Until now, no antiviral treatment has been proven to be effective for the coronavirus disease 2019 (COVID-19). The timing of oxygen therapy, which has rarely been mentioned in the current literature, has a great influence on the symptomatic relief of hypoxemia and seeking medical intervention, especially in situations with limited medical resources. It is worthwhile to find clues from the exploratory use of oxygen and antiviral drugs in Wuhan at the beginning of the COVID-29 pandemic. Therefore, in this study, a retrospective review was carried out to identify the risk factors associated with a severe and fatal illness, including the use of antivirus and timing of oxygen therapy. The main differences in the clinical features of patients with different severities of COVID-19 were described and the risk factors were explored to expand the current recommendations for high-risk groups. Initiation of oxygen treatment less than 2 days after onset after onset of hypoxia symptoms and the use of IFN-a among critically ill patients were significantly associated with lower risk of COVID-19 mortality. Our study highlighted the importance of early oxygen therapy and lend support to the potentially beneficial effects of IFN alpha on critical illness.