Background: In acute respiratory distress syndrome (ARDS) mechanical ventilation is often necessary to manage hypoxia, but mechanical ventilation also induces or aggravates lung injury caused by the respiratory distress. By means of lower volume ventilation and permissive hypercapnia, lung injury is partially prevented; however, other interventions are needed. Helium, in a gas mixture with oxygen (heliox), has a low density and can reduce the flow in narrow airways and allow for lower driving pressures. Methods: PubMed and EMBASE database were used for a systematic search, using terms referring to ARDS or an acute lung injury condition associated with respiratory failure and the intervention. Results: In total 576 papers were retrieved, but the majority had to be excluded. This resulted in only five papers of which three described animal models and two described clinical studies. In the animal models, gas exchange was improved by the use of heliox, while also using less invasive ventilation. Clinical studies show a reduction in work of breathing during heliox ventilation, with a concomitant increase in pH and a decrease in PaCO2 levels compared with oxygen ventilation. Conclusions: There may be a rationale for heliox ventilation in ARDS as an intervention to improve ventilation and reduce work of breathing, but so far the evidence is very marginal. © 2016, Netherlands Society of Intensive Care. All rights reserved.