Introduction: It is highly uncertain whether volatile organic compounds (VOCs) in exhaled breath of critically ill intensive care unit patients are formed in the lung locally, in the air compartment or lung tissue, or elsewhere in the body and transported to the lung via the bloodstream. We compared VOC mixtures in exhaled breath and in air coming from extracorporeal support devices in critically ill patients to address this issue. Methods: First, we investigated whether it was safe to connect an electronic nose (eNose) or a gas sampling pump to extracorporeal support membranes. Then, breath and air from extracorporeal support devices were collected simultaneously for continuous monitoring of VOC mixtures using an eNose. In addition, samples for gas chromatography/mass spectrometry (GC-MS) analysis were taken daily at the two measurement sites. Results: 10 critically ill patients were monitored for a median (interquartile range) duration of 73 (72-113) h; in total, we had 887 h of air sampling. The eNose signals of breath correlated moderately with signals of air from the extracorporeal support devices (R2=0.25-0.44). After GC-MS analysis, 96 VOCs were found both in breath and air from the extracorporeal support devices; of these, 29 (30%) showed a significant correlation (p<0.05) between the two measurement sites, of which 17 were identified. VOCs that did not correlate were found in a higher concentration in breath than in air from the extracorporeal support devices. Conclusion: This study suggests VOC analysis in the extracorporeal circulation is safe, and that VOCs of nonpulmonary origin can be measured in the breath and in the extracorporeal circulation of critically ill patients. For VOCs that did not correlate between the two measurement sites, the breath concentration was higher, suggesting pulmonary production of these molecules in a highly selected population of patients that received extracorporeal support.