Whether prone positioning of patients undergoing mechanical ventilation for COVID-19 pneumonia has benefits over supine positioning is not clear. We conducted a systematic review with meta-analysis to determine whether prone versus supine positioning during ventilation resulted in different outcomes for patients with COVID-19 pneumonia. We searched Ovid Medline, Embase, and Web of Science for prospective and retrospective studies up through April 2023. We included studies that compared outcomes of patients with COVID-19 after ventilation in prone and supine positions. The primary outcomes were three mortality measures: hospital, overall, and intensive care unit (ICU). Secondary outcomes were mechanical ventilation days, intensive care unit (ICU) length of stay, and hospital length of stay. We conducted risk of bias analysis and used meta-analysis software to analyze results. Mean difference (MD) was used for continuous data, and odds ratio (OR) was used for dichotomous data, both with 95% CIs. Significant heterogeneity (I2) was considered if I2was >50%. A statistically significant result was considered if the p-value was <0.05. Of 1787 articles identified, 93 were retrieved, and seven retrospective cohort studies encompassing 5216 patients with COVID-19 were analyzed. ICU mortality was significantly higher in the prone group (OR 2.22, 95% CI 1.43-3.43; p=0.0004). No statistically significant difference was observed between prone and supine groups for hospital mortality (OR, 0.95; 95% CI, 0.66-1.37; p=0.78) or overall mortality (OR, 1.08; 95% CI, 0.72-1.64; p=0.71). Studies that analyzed primary outcomes had significant heterogeneity. Hospital length of stay was significantly higher in the prone than in the supine group (MD, 6.06; 95 % CI, 3.15-8.97; p<0.0001). ICU length of stay and days of mechanical ventilation did not differ between the two groups. In conclusion, mechanical ventilation with prone positioning for all patients with COVID-19 pneumonia may not provide a mortality benefit over supine positioning.