BACKGROUND: An estimated 350 adults develop severe, but potentially reversible respiratory failure in the UK annually. Current management uses intermittent positive pressure ventilation, but barotrauma, volutrauma and oxygen toxicity can prevent lung recovery. An alternative treatment, extracorporeal membrane oxygenation, uses cardio-pulmonary bypass technology to temporarily provide gas exchange, allowing ventilator settings to be reduced. While extracorporeal membrane oxygenation is proven to result in improved outcome when compared to conventional ventilation in neonates with severe respiratory failure, there is currently no good evidence from randomised controlled trials to compare these managements for important clinical outcomes in adults, although evidence from case series is promising. METHODS/DESIGN: The aim of the randomised controlled trial of Conventional ventilatory support vs extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR) is to assess whether, for patients with severe, but potentially reversible, respiratory failure, extracorporeal membrane oxygenation will increase the rate of survival without severe disability ('confined to bed' and 'unable to wash or dress') by six months post-randomisation, and be cost effective from the viewpoints of the NHS and society, compared to conventional ventilatory support. Following assent from a relative, adults (18-65 years) with severe, but potentially reversible, respiratory failure (Murray score >/= 3.0 or hypercapnea with pH < 7.2) will be randomised for consideration of extracorporeal membrane oxygenation at Glenfield Hospital, Leicester or continuing conventional care in a centre providing a high standard of conventional treatment. The central randomisation service will minimise by type of conventional treatment centre, age, duration of high pressure ventilation, hypoxia/hypercapnea, diagnosis and number of organs failed, to ensure balance in key prognostic variables. Extracorporeal membrane oxygenation will not be available for patients meeting entry criteria outside the trial. 180 patients will be recruited to have 80% power to be able to detect a one third reduction in the primary outcome from 65% at 5% level of statistical significance (2-sided test). Secondary outcomes include patient morbidity and health status at 6 months. DISCUSSION: Analysis will be based on intention to treat. A concurrent economic evaluation will also be performed to compare the costs and outcomes of both treatments.