Objective To estimate the feasibility and efficacy of respiratory function score ( RFS)guided ventilator weaning in mechanical ventilated patients with respiratory failure. Methods By a prospective control study,136 patients with acute respiratory failure who had received endotracheal intubation and mechanical ventilation from January 2010 to May 2012 were randomly divided into three group, ie. a RFS-guided 3-4 group ( n=60) , a RFS-guided 5-6 group ( n = 51) , and a traditional group ( n =25) . TheRFS-guided groups underwent ventilator weaning by guidance of RFS 3-4 and 5-6 respectively. The traditional group underwent ventilator weaning by ordinary way. The ventilation and oxygenation index, RFS,direct weaning success rate, total weaning success rate, total mechanical ventilation time, re-intubation rate,and ventilator-associated pneumonia ( VAP) incidence rate were observed.Results The direct weaning success rate in the RFS-guided 3-4 group, the RFS-guided 5-6 group, and the traditional group was 98. 3%( 59/60) , 82. 4% ( 42 /51) , and 100% ( 25 /25) , respectively. The total duration of mechanical ventilation was ( 5. 2 ±2. 5) days, ( 5. 0 ±3. 0) days, and( 7. 5 ±3. 5) days, respectively. the re-intubation rate was 0( 0 /60) , 1. 9% ( 1 /51) , and 0 ( 0/25) , respectively. VAP incidence rate was 11. 7% ( 7/60) , 13. 7%( 7 /51) and 24% ( 6 /25) , respectively. Compared with the traditional group, the direct weaning success rate and total weaning success rate in the RFS-guided 3-4 group were not significant different( P gt;0. 05) , while the total mechanical ventilation time and VAP incidence rate were significantly lower ( P lt; 0. 05) . Compared with the traditional group, the direct weaning success rate and total mechanical ventilation time in the RFSguided 5-6 group were significantly lower ( P lt;0. 05) , but the total weaning success rate was not significantly different ( P gt;0. 05) . Compared with the RFS-guided 5-6 group, the directweaning success rate in the RFSguided 3-4 group was significantly increased. Conclusions Mechanical ventilator weaning of patients with respiratory failure under RFS guidance is safe and feasible. RFS 3-4 guided ventilator weaning can significantly improve the therapeutic effect.