Background: Positive end-expiratory pressure (PEEP) is commonly applied to the ventilated lung to try to improve oxygenation during one-lung ventilation but is an unreliable therapy and occasionally causes arterial oxygen partial pressure (Pao,) to decrease further. The current study examined whether the effects of PEEP on oxygenation depend on the static compliance curve of the lung to which it is applied. Methods: Forty-two adults undergoing thoracic surgery were studied during stable, open-chest, one-lung ventilation. Arterial blood gasses were measured during two-lung ventilation and one-lung ventilation before, during, and after the application of 5 cm H2O PEEP to the ventilated lung. The plateau end-expiratory pressure and static compliance curve of the ventilated lung were measured with and without applied PEEP, and the lower inflection point was determined from the compliance curve. Results: Mean (+/- SD) Pao, values, with a fraction of inspired oxygen of 1.0, were not different during one-lung ventilation before (192 +/- 91 mmHg), during (190 +/- 90), or after (205 +/- 79) the addition of 5 cm H2O PEEP. The mean plateau end-expiratory pressure increased from 4.2 to 6.8 cm H2O with the application of 5 cm H2O PEEP and decreased to 4.5 cm H2O when 5 cm H2O PEEP was removed. Six patients showed a clinically useful (> 20%) increase in Pao(2) with 5 cm H2O PEEP, and nine patients had a greater than 20% decrease in Pao2. The change in Pao(2) with the application of 5 CM H2O PEEP correlated in an inverse fashion with the change in the gradient between the end-expiratory pressure and the pressure at the lower inflection point (r = 0.76). The subgroup of patients with a Pao, during two-lung ventilation that was less than the mean (365 mmHg) and an end-expiratory pressure during one-lung ventilation without applied PEEP less than the mean were more likely to have an increase in Pao, when 5 cm H2O PEEP was applied. Conclusions: The effects of the application of external 5 cm H2O PEEP on oxygenation during one-lung ventilation correspond to individual changes in the relation between the plateau end-expiratory pressure and the inflection point of the static compliance curve. When the application of PEEP causes the end-expiratory pressure to Increase from a low level toward the Inflection point, oxygenation is likely to improve. Conversely, if the addition of PEEP causes an increased inflation of the ventilated lung that raises the equilibrium end-expiratory pressure beyond the inflection point, oxygenation Is likely to deteriorate.