Clearance of secretions remains a challenge in ventilated patients. Despite high-frequency percussive ventilation (HFPV) showing benefits in patients with cystic fibrosis and neuromuscular disorders, very little is known about its effects on other patient categories. Therefore, we designed a physiological pilot study investigating the effects on lung aeration and gas exchange of short HFPV cycles in tracheostomized patients undergoing mechanical ventilation. Electrical impedance tomography (EIT) was recorded at baseline (T0) by a belt wrapped around the patient's chest, followed by the HFPV cycle lasting 10 min. EIT data was collected again after the HFPV cycle (T1) as well as after 1 h (T2) and 3 h (T3) from T0. Variation from baseline of end-expiratory lung impedance (∆EELI), tidal variation (TIV) and global inhomogeneity index (GI) were computed. Arterial blood was also taken for gas analysis. HFPV cycle significantly improved the ∆EELI at T1, T2 and T3 when compared to baseline (p < 0.05 for all comparisons). The ratio between arterial partial pressure and inspired fraction of oxygen (PaO2/FiO2) also increased after the treatment (p < 0.001 for all comparison) whereas TIV (p = 0.132) and GI (p = 0.114) remained unchanged. Short cycles of HFPV superimposed to mechanical ventilation promoted alveolar recruitment, as suggested by improved ∆EELI, and improved oxygenation in tracheostomized patients with high load of secretion.Trial RegistrationProspectively registered on www.clinicaltrials.gov (NCT05200507; dated 6th January 2022).Supplementary InformationThe online version contains supplementary material available at 10.1007/s10877-022-00970-7.