ObjectiveTo explore the effect of prone position ventilation (PPV) on respiratory mechanics and prognosis in patients with acute respiratory distress syndrome (ARDS) concurrent with interstitial lung disease (ILD). Methods The data of 36 severe ARDS patients admitted to Department of Critical Care Medicine of the First Affiliated Hospital of Guangzhou Medical University from February 2013 to January 2015, were retrospectively analyzed. They were then divided into two groups according to the presence of ILD or not. The changes in respiratory mechanics and oxygenation indexes were compared before and after PPV treatment in all the patients. Kaplan-Meier method was applied to draw the 60-day survival curves of both groups.Results There were 17 cases with ILD among these 36 severe ARDS patients.① No significant difference was found in baseline data between ILD group and non-ILD group.② Respiratory mechanics and oxygenation pre-PPV and post-PPV: compared with pre-PPV, oxygenation index (PaO2/FiO2, mmHg, 1 mmHg = 0.133 kPa) post-PPV was significantly increased in both groups [ILD group : 132.0 (93.5, 172.0) vs. 118.7 (92.0, 147.8); non-ILD group: 126.1 (100.9, 170.0) vs. 109.2 (89.0, 135.0), bothP< 0.05]. Compared with pre-PPV, positive end-expiratory pressure (PEEP, cmH2O,1 cmH2O = 0.098kPa) post-PPV was significantly higher in ILD group [10.0 (10.0, 12.0) vs. 10.0 (9.2, 12.0),P< 0.05], and respiratory rate (RR, times/min) was significantly lower in non-ILD group [24.5 (22.0, 27.0) vs. 25.5 (22.8, 28.0),P< 0.05]. The compliance of the respiratory system (Crs, mL/cmH2O) post-PPV in non-ILD group was significantly lower than that of the ILD group [19.7 (16.1, 28.6) vs. 23.0 (19.0, 29.7),P< 0.05].③ Respiratory mechanics and oxygenation pre-PPV and post-PPV in total: after all the PPV therapy, PaO2/FiO2 (mmHg) was significantly increased in non-ILD group [135.0 (86.0, 200.0) vs. 97.4 (69.2, 127.5), P< 0.05], PaO2/FiO2 after all the PPV therapy in non-ILD group was also higher than that in ILD group [135.0 (86.0, 200.0) vs. 78.7 (59.3, 114.9),P< 0.05]. No significant difference in Crs (mL/cmH2O) before PPV treatment was found between non-ILD and ILD groups [24.3 (15.9, 48.9) vs. 18.9 (12.7, 27.3),P> 0.05], and Crs was lower after PPV treatment in both groups, but without significant difference [non-ILD group: 22.7 (15.2, 27.1) vs. 24.3 (15.9, 48.9); ILD group: 16.2 (12.8, 25.6) vs. 18.9 (12.7, 27.3), bothP> 0.05].④ The 60-day mortality in ILD group was significantly higher than that in non-ILD group [88.2% (15/17) vs. 57.9% (11/19),P = 0.047). It was shown by Kaplan-Meier curves that 60-day survival patients in ILD group was significantly lower than those in non-ILD group (χ2 = 5.658,P = 0.017). Conclusions PPV can improve oxygenation in severe ARDS. Compared with non-ILD group, though the compliance of respiratory system in ILD group is increased during PPV, long-term effect is better in non-ILD group.