ObjectiveTo investigate the efficacy of bundle treatment on patients with moderate or severe acute respiratory distress syndrome (ARDS).Methods A multicenter prospective observational study comparing the result of historical treatment strategy and bundle treatment was conducted. According to the new Berlin standard of definition, 73 patients with moderate or severe ARDS due to pulmonary factors, age from 18 to 65 years, admitted to Department of Critical Care Medicine of Taian Central Hospital and Handan Central Hospital were enrolled. Thirty-three patients admitted during September 2012 to May 2014 (prospective observation period) were enrolled as the bundle treatment group. Forty patients with matched disease history admitted from January 2010 to August 2012 were enrolled as the control group. The patients in bundle treatment group received bundle treatment based on the treatment strategy of primary diseases. Bundle treatment included restrictive fluid management, respiratory support, high-dose ambroxol combined with Xuebijing injection, prevention of ventilation associated pneumonia (VAP), individualized sedation plan, installation of continuous blood purification treatment for critical patients. A special team was organized to ensure the successful implementation of all bundle measures. The acute physiology and chronic health evaluationⅡ (APACHEⅡ) score, oxygenation index, duration of mechanical ventilation, the length of intensive care unit (ICU) stay, incidence of VAP, and 28-day mortality 5 days after treatment were compared between two groups.Results There were no significant differences in basic characteristics of patients between the two groups, including gender, age, etiology, severity, etc. (allP> 0.05) with comparability. Compared with the control group, there was no significant difference in APACHEⅡ score 5 days after treatment in bundle treatment group (15.1±2.8 vs. 16.2±3.0,t = 1.618,P = 0.110). Compared with control group, oxygenation index in bundle treatment group was significantly improved [mmHg (1 mmHg = 0.133 kPa): 135.4±34.5 vs. 117.1±34.2,t = -2.273,P = 0.026), the duration of mechanical ventilation was obviously reduced (days: 8.70±2.50 vs. 10.10±2.67,t = 2.308,P = 0.024), incidence of VAP was significantly lower [18.2% (6/33) vs. 32.5% (13/40),χ2 = 5.027,P = 0.025], and 28-day mortality rate was obviously lowered [24.2% (8/33) vs. 37.5% (15/40),χ2 = 4.372,P = 0.037], the length of ICU stay shown no statistical difference (days:10.40±1.94 vs. 11.30±2.34,t = 1.620,P = 0.110).Conclusion Implementation of bundle treatment can significantly shorten the duration of mechanical ventilation, reduce the incidence of VAP, and improve the prognosis of patients.