The aim of hyperinflation in the ventilated intensive care unit patient is to increase oxygenation, reverse lung collapse and clear sputum. The efficacy and consistency of manual hyperventilation is well supported in the literature, but there is limited published evidence supporting hyperventilation utilising a ventilator. Despite this, a recent survey established that almost 40% of Australian tertiary intensive care units utilise ventilator hyperinflation. The aim of this non-inferiority cross-over study was to determine whether ventilator hyperinflation was as effective as manual hyperinflation in clearing sputum from patients receiving mechanical ventilation using a prescriptive ventilator hyperinflation protocol. Forty-six patients received two randomly ordered physiotherapy treatments on the same day by the same physiotherapist. The efficacy of the hyperinflation modes was measured by sputum wet weight. Secondary measures included compliance, tidal volume, airway pressure and PaO2/FiO2 ratio. There was no difference in wet weight of sputum cleared using ventilator hyperinflation or manual hyperinflation (mean 3.2 g, P=0.989). Further, no difference in compliance (P=0.823), tidal volume (P=0.219), heart rate (P=0.579), respiratory rate (P=0.929) or mean arterial pressure (P=0.593) was detected. A statistically significant difference was seen in mean airway pressure (P=0.002) between techniques. The effect of techniques on the PaO2/FiO2 response ratio was dependent on time (interaction P=0.024). Physiotherapy using ventilator hyperinflation cleared a comparable amount of sputum and was as safe as manual hyperinflation. This research describes a ventilator hyperinflation protocol that will serve as a platform for continued discussion, research and development of its application in ventilated patients.