Major trauma patients who are intubated and ventilated are exposed to the potential risk of iatrogenic hypercapnic and hypocapnic physiological stress. In the pre-hospital setting, end-tidal capnography is used as a practical means of estimating arterial carbon dioxide concentrations and to guide the adequacy of ventilation. In our study, potentially deleterious hypercapnia (mean 47 mmHg, range 26 to 83 mmHg) due to hypoventilation was demonstrated in 49% of 100 intubated major trauma patients arriving at a major Australian trauma centre. A mean gradient of 15 mmHg arterial to end-tidal carbon dioxide concentration difference was found, highlighting the limitations of capnography in this setting. Moreover, 80% of the patients in the study had a head injury. Physiological deadspace due to hypovolaemia in these patients is commonly thought to contribute to the increased arterial to end-tidal carbon dioxide gradient in trauma patients. However in this study, scene and arrival patient hypoxia was more predictive of hypoventilation and an increased arterial to end-tidal carbon dioxide gradient than physiological markers of shock. Greater vigilance for hypercapnia in intubated trauma patients is required. Additionally, a larger study may confirm that lower end-tidal carbon dioxide levels could be safely targeted in the pre-hospital and emergency department ventilation strategies of the subgroup of major trauma patients with scene hypoxia.