The present study compares the changes in ventilation in response to sustained hypobaric hypoxia and acute normobaric hypoxia between subjects susceptible to high altitude pulmonary edema (HAPE-S) and control subjects (C-S). Seven HAPE-S and five C-S were exposed to simulated high altitude of 4000 m for 23 h in a hypobaric chamber. Resting minute ventilation (VE), tidal volume (VT), and respiratory frequency (fR), as well as the end-tidal partial pressures of oxygen (PETO2) and carbon dioxide (PETCO2) were measured in all subjects sitting in a standardized position. Six measurement periods were recorded: ZH1 at 450 m at Zurich level, HA1 on attaining 3600 m altitude, HA2 after 20 min at 4000 m, HA3 after 21 h and HA4 after 23 h at 4000 m altitude, and ZH2 immediately after recompression to Zurich level. At ZH1 and HA3, the measurements were first done in lying, then in sitting, and afterwards in standing. Peripheral arterial oxygen saturation (SaO2) was continuously recorded. All respiratory parameters were also measured during exercise lasting 30 min, the work load being 50% of maximal oxygen consumption (VO2max) at Zurich level and 26% of the Zurich VO2max at 4000 m. VE, PETO2 and PETCO2 did not significantly differ between HAPE-S and C-S at rest and during exercise periods at Zurich level and at high altitude. However, SaO2 was significantly lower in HAPE-S than in C-S at rest and during exercise at 4000 m. Breathing through the mouthpiece during ventilation measurements increased significantly the SaO2 in HAPE-S in posture tests at HA3. This effect was most pronounced in the supine posture, in which HAPE-S had the lowest SaO2 values. These data provide evidence that (1) gas exchange might be impaired on the level of ventilation-perfusion mismatch or due to diffusion limitation in HAPE-S during the first 23 h of exposure to a simulated altitude of 4000 m, and (2) contrary to C-S, the SaO2 in HAPE-S is significantly affected by body position and by mouthpiece breathing.