Objective: The survival benefit of prone positioning during mechanical ventilation for acute respiratory distress syndrome (ARDS) has been a matter of debate. We performed an up-to-date meta-analysis on this topic and elucidated the effect of prone positioning on overall mortality and associated complications. Methods: Randomized controlled trials (RCTs) comparing overall mortality of prone-versus-supine positioning in ARDS patients were included. Data were extracted for populations, interventions, outcomes and risk of bias. The prespecified primary endpoint was overall mortality, using the longest available follow-up in each study. The odds ratio (OR) with 95% confidence interval (CI) was the effect measure. Results: This analysis included 11 RCTs, 2,246 total adult patients, and 1,142 patients ventilated in the prone position. Prone positioning during ventilation significantly reduced overall mortality in the random effect model (OR: 0.77; 95% CI: 0.59-0.99). In addition, the effects were measured for the subgroup in which the duration of prone positioning was ＞10 hours/session, compared to the subgroup with a short-term duration of prone positioning (OR: 0.62; 95% CI: 0.48-0.79). Prone positioning was significantly associated with pressure ulcers (OR: 1.49; 95% CI: 1.18-1.89) and major airway problems (OR: 1.55; 95% CI: 1.10-2.17). Conclusions: Ventilation in the prone position significantly reduced overall mortality in patients with severe ARDS. An adequate duration of prone positioning was significantly associated with a reduction in overall mortality. Objective: The survival benefit of prone positioning during mechanical ventilation for acute respiratory distress syndrome (ARDS) has been a matter of debate. We performed an up-to-date meta-analysis on this topic and elucidated the effect of prone positioning on overall mortality and associated complications. Methods: Randomized controlled trials (RCTs) comparing overall mortality of prone-versus-supine positioning in ARDS patients were included. Data were extracted for populations, interventions, outcomes and risk of bias. The prespecified primary endpoint was overall mortality, using the longest available follow-up in each study. The odds ratio (OR) with 95% confidence interval (CI) was the effect measure. Results: This analysis included 11 RCTs, 2,246 total adult patients, and 1,142 patients ventilated in the prone position. Prone positioning during ventilation significantly reduced overall mortality in the random effect model (OR: 0.77; 95% CI: 0.59-0.99). In addition, the effects were measured for the subgroup in which the duration of prone positioning was ＞10 hours/session, compared to the subgroup with a short-term duration of prone positioning (OR: 0.62; 95% CI: 0.48-0.79). Prone positioning was significantly associated with pressure ulcers (OR: 1.49; 95% CI: 1.18-1.89) and major airway problems (OR: 1.55; 95% CI: 1.10-2.17). Conclusions: Ventilation in the prone position significantly reduced overall mortality in patients with severe ARDS. An adequate duration of prone positioning was significantly associated with a reduction in overall mortality.