The use of 100% oxygen to determine intrapulmonary shunting has been widely advocated. This study was performed to determine the clinical application of this technique in critically ill patients on PEEP. Determinations of intrapulmonary shunting using FIO2 of 0.45 and 1.0 were performed on 18 patients. Machine error was also calculated. Shunt calculations increased by an average of 52% (29% corrected for machine error) with the use of an FIO2 of 1.0 and returned to previous levels when an FIO2 of 0.45 was reinstituted. There was no statistical difference in shunt increase between patients on high (≥15 cm H2O) or low (<15 cm H2O) PEEP. The use of 100% oxygen to calculate intrapulmonary shunting in patients on PEEP is misleading in both physiological and methodological terms.