Abstract Background End-expiratory lung volume measurement by the nitrogen washin-washout technique (EELV WI-WO ) may help titrating positive end-expiratory pressure (PEEP) during acute respiratory distress syndrome (ARDS). Validation of this technique has been previously performed using computed tomography (EELV CT ), but at mild PEEP levels, and relatively low fraction of inspired oxygen (FiO 2 ), which may have insufficiently challenged the validity of this technique. The aims of this study were (1) to evaluate the reliability of EELV WI-WO measurements at different PEEP and V T during experimental ARDS and (2) to evaluate trending ability of EELV WI-WO to detect EELV changes over time. Methods ARDS was induced in 14 piglets by saline lavage. Optimal PEEP was selected during a decremental PEEP trial, based on best compliance, best EELV WI-WO , or a PEEP-FiO 2 table. Eight V T (4 to 20 mL · kg -1 ) were finally applied at optimal PEEP. EELV WI-WO and EELV CT were determined after ARDS onset, at variable PEEP and V T . Results EELV WI-WO underestimated EELV CT with a non-constant linear bias, as it decreased with increasing EELV. Limits of agreement for bias were ±398 mL. Bias between methods was greater at high PEEP, and further increased when high PEEP was combined with low V T . Concordance rate of EELV changes between consecutive measurements was fair (79%). Diagnostic accuracy was good for detection of absolute EELV changes above 200 mL (AUC = 0.79). Conclusions The reliability of the WI-WO technique is critically dependent on ventilatory settings, but sufficient to accurately detect EELV change greater than 200 mL.