Objective To investigate the risk factors for early progression in patients with acute respiratory distress syndrome (ARDS), and to provide a reference for early detection and intervention of high-risk patients with ARDS progression. Methods Data from multicenter mechanically ventilated patients with mild to moderate ARDS were retrospectively analyzed. According to the severity grade of 72 h ARDS, the patients were divided into an early progressive group and a non-progressive group. Chi-square test was used to compare the risk factors of ARDS patients and the prognosis of the two groups were analyzed by Logistic regression. Results A total of 355 patients with mild to moderate ARDS were included in invasive mechanical ventilation, of which 97 patients (27.3%) progressed after 72 hours. 78.4% were female in the progressive group and 64.0% were female in the non-progressive group. Compared with the non-progressive group, the patients with ARDS in the progressive group had shorter 28-day no mechanical ventilation, higher ICU mortality, and lower survival rate at 30 days and 60 days（P<0.05）, but there was no significant difference in the length of ICU stay between the two groups (P>0.05). Univariate and multivariate regression analysis showed that the patients with ARDS in the progressive group had lower baseline oxygenation index (OR=0.979, 95%CI 0.961 - 0.986, P<0.01), higher peak airway pressure (OR=1.068, 95%CI 1.017 - 1.121, P<0.01), higher lactate level (OR=1.224, 95%CI 1.057 - 1.417, P<0.01), higher tidal volume (OR=1.159, 95%CI 1.002 - 1.341, P<0.05), higher age (OR=1.373, 95%CI 1.051 - 1.082, P<0.01), and more male patients (OR=2.583, 95%CI 1.336 - 4.995, P<0.05). Conclusions Early progression is common in mild to moderate ARDS patients with mechanical ventilation. The progressive group has shorter duration of 28 days without mechanical ventilation, higher ICU mortality and lower 30-day and 60-day survival rate than the non-progressive group. Male, low baseline oxygenation index levels, high peak airway pressure, tidal volume, lactate levels, and higher age are risk factors for early progression in patients with mild to moderate ARDS.