Acute mountain sickness (AMS) is a common problem while ascending at high altitude. AMS may progress rapidly to fatal results if the acclimatization process fails or symptoms are neglected and the ascent continues. Extensively reduced arterial oxygen saturation at rest (R-Spo₂) has been proposed as an indicator of inadequate acclimatization and impending AMS. We hypothesized that climbers less likely to develop AMS on further ascent would have higher Spo₂ immediately after exercise (Ex-Spo₂) at high altitudes than their counterparts and that these postexercise measurements would provide additional value for resting measurements to plan safe ascent. The study was conducted during eight expeditions with 83 ascents. We measured R-Spo₂ and Ex-Spo₂ after moderate daily exercise [50 m walking, target heart rate (HR) 150 bpm] at altitudes of 2400 to 5300 m during ascent. The Lake Louise Questionnaire was used in the diagnosis of AMS. Ex-Spo₂ was lower at all altitudes among those climbers suffering from AMS during the expeditions than among those climbers who did not get AMS at any altitude during the expeditions. Reduced R-Spo₂ and Ex-Spo₂ measured at altitudes of 3500 and 4300 m seem to predict impending AMS at altitudes of 4300 m (p < 0.05 and p < 0.01) and 5300 m (both p < 0.01). Elevated resting HR did not predict impending AMS at these altitudes. Better aerobic capacity, younger age, and higher body mass index (BMI) were also associated with AMS (all p < 0.01). In conclusion, those climbers who successfully maintain their oxygen saturation at rest, especially during exercise, most likely do not develop AMS. The results suggest that daily evaluation of Spo₂ during ascent both at rest and during exercise can help to identify a population that does well at altitude.