Compensation for hypoxia at altitude through increased blood flow helps maintain oxygen delivery (Wolff, Adv Exp Med Biol 599:169-182, 2007). However, the relationship of acute mountain sickness (AMS) to the hypoxia of altitude is poorly understood. In the present study arterial oxygen saturation (SaO 2) and heart rate (HR) were measured twice daily at altitude in eight subjects both at rest (SaO2rest; HRrest) and separately during exercise (SaO2ex; HRex). Seven subjects completed a 28-day expedition (one subject only 20 days) at altitudes 3,324-5,176 m (55-68 kPa). The AMS score (Hackett PH, Oeltz O (1992) The Lake Louis Consensus on the definition and quantification of altitude illness. In: Sutton JR, Coates G, Houston SC (eds) Hypoxia and mountain medicine. Queen City Printers, Burlington, pp 327-330) was recorded daily. In seven of the eight subjects HRrest correlated with SaO 2rest (p ≤ 0.01). HR × SaO2 a surrogate for oxygen delivery (DO2) remained constant. Individual mean SaO 2rest, HRrest, SaO2ex, HRex and AMS scores were calculated (SaO2rest 81.3-93.2%; HRrest 70-106 bpm. Mean individual SaO 2 values for exercise (SaO2ex) correlated with, but were significantly lower than SaO2rest (SaO2ex = 1.3363 × SaO2rest - 33.734, r = 0.975, p < 0.001). Mean AMS scores correlated with mean SaO2rest (r = 0.926, p = 0.002) and SaO 2ex (r = 0.917, p = 0.003) in the seven 28-day subjects. AMS is therefore related to SaO2, which, in turn, indicates (inversely) the degree of respiratory compensation for ambient hypoxia. An earlier version of this work was presented to the UK Physiological Society (Parks et al., Proc Physiol Soc 14:PC2, 2009).