Background:Invasive mechanical ventilation is a crucial intervention for the management of critical COVID-19 patients. However, the impact of prone position (PP) on patients undergoing invasive mechanical ventilation remains uncertain. This study aims to investigate the potential benefits of PP in terms of improving the oxygenation index and prognosis. Methods:A total of 289 critically ill COVID-19 patients were retrospectively gathered from ICU of three general hospitals located in Taizhou, Zhejiang Province from December 1, 2022 to February 1, 2023, all patients were invasive mechanical ventilated. 78 cases of PP group and 78 cases of non-PP group were matched with propensity score matching. The study compared clinical data, laboratory results, and hospitalization survival rate between two groups of patients. Furthermore, we compared the laboratory results, and hospitalization survival across varying numbers of PPs. Results:The mean oxygenation index exhibited a greater increase in PP group compared to non-PP group (48 vs 32mmHg). Hospital survivors of PP group (63 patients) demonstrated more substantial decrease in their Sequential Organ Failure Assessment scores and C-reactive protein levels compared to non-PP group (51 patients). The initial PP cycle resulted in a significant elevation of the oxygenation index by 30.8 (-16.4,46.9) mmHg; the second PP cycle demonstrated a maximum increase of 56.3 (13.0,92.8) mmHg. A higher frequency of PP yielded a more pronounced improvement in oxygenation and had the potential to enhance the survival rate. Additionally, the eight patients who was improvements in their oxygenation index during the initial three PP cycles and successfully survived had higher lymphocyte counts (0.2-2.4) vs (0.1-0.5)×10 ⁹/L and a longer duration of PP (53.0-113.5) vs (36.0-98.5)h. Conclusion:PP has the potential to enhance the oxygenation index and survival rates among critically ill COVID-19 patients invasive mechanical ventilated. Notably, a positive correlation was observed between the frequency of PP and the improvement of oxygenation. Our investigation further revealed that the efficacy of the PP may be influenced by lymphocyte count and duration of PP.