Background: Following endotracheal intubation, clearing secretions above the endotracheal tube cuff decreases the incidence of ventilator-associated pneumonia (VAP); therefore, subglottic secretion drainage (SSD) is widely advocated. Our group developed a novel technique to remove the subglottic secretions, the rapid-flow expulsion maneuver (RFEM). The objective of this study was to explore the effectiveness and safety of RFEM compared with SSD. Methods: This study was a single-center, prospective, randomized and controlled trial, conducted at Respiratory Intensive Care Unit (ICU) of Beijing Chao-Yang Hospital, a university-affiliated tertiary hospital. The primary outcome was the incidence of VAP, assessed for non-inferiority. Results: Patients with an endotracheal tube allowing drainage of subglottic secretions (n = 241) were randomly assigned to either the RFEM group (n = 120) or SSD group (n = 121). Eleven patients (9.17%) in the RFEM group and 13 (10.74%) in the SSD group developed VAP (difference, - 1.59; 95% confidence interval [CI] [- 9.20 6.03]), as the upper limit of 95% CI was not greater than the pre-defined non-inferiority limit (10%), RFEM was declared non-inferior to SSD. There were no statistically significant differences in the duration of mechanical ventilation, ICU mortality, or ICU length of stay and costs between groups. In terms of safety, no accidental extubation or maneuver-related barotrauma occurred in the RFEM group. The incidence of post-extubation laryngeal edema and reintubation was similar in both groups. Conclusions: RFEM is effective and safe, with non-inferiority compared to SSD in terms of the incidence of VAP. RFEM could be an alternative method in first-line treatment of respiratory ICU patients.