Objective: Ventilator-assisted preoxygenation (VAPOX) is a method of preoxygenation and apnoeic ventilation which has been tried in hospital setting. We aimed to describe VAPOX during intubation of critically unwell patients in aeromedical retrieval setting. Methods: Retrospective observational study of VAPOX performed at LifeFlight Retrieval Medicine (LRM) between January 2018 and December 2022 across Queensland, Australia. Demographic and clinical data were recorded. Descriptive statistics and paired Student's t-tests were used to evaluate the efficacy of VAPOX on oxygen saturation (SpO2). Results: VAPOX was used in 40 patients. Diagnoses included pneumonia (n = 11), COPD (n = 6) and neurological (n = 7). Patients were intubated in hospital (n = 36), in helicopter (n = 2) and ambulance (n = 2). Median VAPOX settings were: positive end-expiratory pressure 6 (IQR 5–9), pressure support 10 (IQR 10–14) and back up respiratory rate 14 (IQR 11–18). Twelve agitated patients underwent delayed sequence induction with ketamine. There was a statistically significant increase in SpO2 after application of VAPOX (P < 0.001), followed by a slight decrease after intubation (P = 0.006). Mean SpO2 were significantly improved after intubation compared with on arrival of LRM (P = 0.016). Hypotension was present prior to VAPOX (n = 13), during VAPOX (n = 2) and post-intubation (n = 15). Two patients had cardiac arrest. Three patients were started on VAPOX but subsequently failed. There were no significant oxygen depletion or aspiration events. Conclusion: VAPOX can be considered for pre-intubation optimisation in the retrieval environment. The incidence of post-intubation critical hypoxia was low, and hypotension was high. Pre-intubation respiratory physiology can be optimised by delivering variable pressure supported minute ventilation, achieving a low incidence of critical hypoxia.