ABSTRACT.The use of a multiple gas rebreathing method for the measurement of cardiopulmonary function in mechanically ventilated neonates was evaluated. The following indices of cardiopulmonary function were assessed in 20 piglets (mean weight, 2.3 kg): 1) pulmonary capillary blood flow(Qc),2) diffusing capacity for carbon monoxide (DLco), 3) lung gas volume (FRC), 4) oxygen consumption(Vo2),and 5) volume of the pulmonary tissues and capillaries (VTPC), the latter an estimate of total lung water. During mechanical ventilation at zero end expiratory pressure, all rebreathing parameters correlated well with body weight. Additionally, a good correlation(r =0.81, slope = 0.99) between VTPC and postmortem estimate of total lung water was observed. The effect of ventilation with positive end expiratory pressure (PEEP) was then studied in 10 piglets. On increasing PEEP from zero to 15 cm H20, FRC significantly increased by 208%,Qcsignificantly decreased by 60%, and no changes in VTPC occurred. Seven piglets were then studied after induction of lung injury by oleic acid infusion. Compared with the pre-oleic acid infusion values, all the rebreathing variables decreased during ventilation without PEEP. Unlike the situation with the normal piglets, when PEEP was increased from zero to 10 cm H2O in the oleic acid-infused piglets, the values for FRC and VTPC significantly increased. Mean VTPC at 10 cm H2O was 20 ± 2 ml/kg which correlated well (r= 0.93) with the postmortem total lung water value of 19 ± 1 g/kg. Thus, multiple gas rebreathing methodology is applicable to studies using Small animals. The observation that the applicartion of PEEP in lung injury increased the accuracy of the VIPC measurement suggests that PEEP improves ventilation of injured lung segments.