Background Catheter suction (CS), the standard method for airway secretion management in tracheostomized or intubated patients, is invasive and has significant hemodynamic and traumatic side effects. In-line mechanical insufflation-exsufflation (IL-MIE) is a new, non-invasive technology that clears secretions by simulating coughs without interrupting ongoing mechanical ventilation. It is not known whether IL-MIE can be safely and effectively used as an alternative to CS in these ventilated patients. Methods A randomized controlled study was conducted comparing a standard protocol of CS with automatic IL-MIE (CoughSync, Ruxin Medical Systems, Beijing) performed every 30 minutes, with CS added only if needed, in post-operative mechanically ventilated patients. Results Over 8 hours, the IL-MIE cohort required significantly fewer CS treatments per patient than the control cohort (mean 0.4 vs. 2.6, p < 0.001, n = 60 for both cohorts). Seventy-three percent of the IL-MIE subjects required no CS at all, compared to 2% in the control group (p < 0.001). At 8 hours, IL-MIE subjects had a significantly lower heart rate than control subjects (mean 90 vs. 96, p = 0.047), implying a hemodynamic advantage to IL-MIE. No significant adverse events were associated with IL-MIE. Conclusions IL-MIE minimizes the need for invasive CS without detriment to ventilatory management in mechanically ventilated patients.