Background:Prone position has already been demonstrated to improve survival in non-COVID acute respiratory distress syndrome. It has been widely performed in COVID-19 patients with respiratory failure, both in non-intubated and intubated patients. However, the beneficial effect of the prone position in COVID-19 pneumonia still remains unclear. Therefore, we aimed to evaluate the effectiveness and safety of the prone position compared with the non-prone in COVID-19 patients. Methods:We searched the MEDLINE, EMBASE, and Cochrane databases, as well as one Korean domestic database, on July 9, 2021, and updated the search monthly to February 10, 2022. Studies that compared prone and non-prone positions in patients with COVID-19 were eligible for inclusion. The primary outcomes were mortality, need for intubation, and adverse events. The secondary outcomes were the length of stay (LOS) in the hospital or intensive care unit (ICU), ICU-free days, and ventilator-fee days. Subgroup analysis was performed based on the oxygen delivery methods. Results:Of the 1,179 records identified, 4 randomized controlled trials (RCTs) and 16 cohort studies were eligible. In cohort studies, the mortality was not different between the prone and non-prone groups in intubated patients, but the prone position showed a significant survival benefit in the non-intubated patient group regardless of the oxygen delivery method (13 studies, n=2,519; relative risk [RR] 0.59, 95% CI 0.47 to 0.76, P<0.0001, I2=48%). In addition, the prone position reduced the intubation rate in RCTs (3 studies, n=1,256, RR 0.83, 95% CI 0.71 to 0.97, P=0.02) compared with the non-prone position. In both RCTs and cohort studies, there were no significant differences in LOS in the ICU or hospital, ICU-free days, or ventilator-free days between the prone and non-prone positions. Adverse events were mild and similar between the two groups.Conclusion:In non-intubated patients with COVID-19, prone positioning reduced the risk of intubation in patients requiring a high-flow oxygen system and improved survival with similar adverse event rates. Therefore, the prone position should be encouraged in non-intubated COVID-19 patients. However, insufficient evidence supports the beneficial effects of prone positioning in intubated patients.Registration: This study was registered in the Prospective Register of Systematic Reviews on February 16, 2022 (registration number: CRD42022311150).