BACKGROUND: The measurement of functional residual capacity (FRC) in ventilated patients could help track the extent of acute lung disease, monitor recruitment of unstable lung units, or guide the use of PEEP. Quantitative analysis of computed tomography (CT) images of the lungs is currently the accepted standard for FRC measurement (FRC-CT), but is impractical for routine use. Gas dilution and gas tracer technologies, while attractive for research applications, require specialized equipment and skills missing from the clinical setting. We simultaneously evaluated FRC-CT and FRC determined by a ventilator-incorporated wash-in/wash-out (FRC-WI/WO) method in an animal model of unilateral pleural effusion that varied the fluid volume instilled and the applied PEEP. METHODS: A swine model (n = 6) of unilateral pleural effusion was created by injecting boluses of radio-opaque fluid (iopromide) (13 mL/kg and then 26 mL/kg) into the right thoracic cavity. FRC-CT and FRC-WI/WO were simultaneously obtained, at 2 PEEP levels, at baseline and at both pleural-effusion volumes. RESULTS: A correlation coefficient (r2) of 0.89 between FRC-CT and FRC-WI/WO revealed concordance between the techniques, with directional agreement and acceptable bias and precision under all tested conditions. CONCLUSIONS: We found excellent concordance between FRC-WI/WO and FRC-CT in an animal model of unilateral pleural effusion that stressed the capability of this technology. The technical advantage of the wash-in/wash-out technique is its incorporation into ventilator operation without requiring adjustments to ventilation.