Preliminary studies on sleep of patients with congenital heart disease and Eisenmenger's syndrome (ES) at our institution demonstrated nocturnal worsening arterial unsaturation, which appeared to be a body position-related phenomenon. To investigate the potential effect of body position on gas exchange in ES, we carried out a prospective study of 28 patients (mean age, 34.8 +/- 11.7 yr) with established ES due to congenital heart disease. In every patient, arterial blood gases were performed during both sitting and supine positions under three different conditions: room air, while breathing 100% oxygen, and after breathing oxygen at a flow rate of 3 L/min through nasal prongs. Alveolar oxygen pressure (PaO2) for the calculation of alveolar-arterial oxygen tension differences (AaPO2) was derived from the alveolar gas equation using PaCO2 and assuming R = 1. We used paired t test, repeated-measures two-way ANOVA with Bonferroni's test, and regression analysis. From sitting to supine position on room air, there was a significant decrease in PaO2 (from 52.5 +/- 7.5 to 47.5 +/- 5.5 mm Hg; p < 0. 001) and SaO2 (from 86.7 +/- 4.6 to 83.3 +/- 4.9%; p < 0.001), both of which were corrected by nasal O2 (to 68.2 +/- 21 mm Hg and to 92 +/- 4%, respectively, p < 0.005). PaCO2 and pH remained unchanged. The magnitude of the change in PaO2 correlated with the change in AaPO2 on room air (r = 0.77; p < 0.01) but not with the change in AaPO2 on 100% oxygen. It is concluded that in adult patients with ES there is a significant decrease in PaO2 and SaO2 when they change from the sitting to the supine position. A ventilation-perfusion (V/Q) distribution abnormality and/or a diffusion limitation phenomenon rather than an increase in true shunt may be the mechanisms responsible for this finding. The response to nasal O 2 we observed warrants a trial with long-term nocturnal oxygen therapy in these patients.