The normal relationship between red cell mass measured, with 51chromium-labeled red cells, and arterial oxygen saturation (SaO2) over the range from 97.3 to 83.4% was examined by studying 73 normal men residing at sea level and altitudes of 1600 and 3100 m. A simple, linear relationship between SaO2 and red cell mass was found over the entire range (r = - 0.7524, P < 0.001). In contrast, a correlation between red cell mass and arterial O2 tension was found only over the lower half of the range of O2 tensions where SaO2 was also decreased (r = - 0.7731, P < 0.005). This suggested that O2 saturation rather than tension is the more important determinant of the erythropoietic response to chronic hypoxia. If this response is regulated by tissue O2 tension, then it will be influenced by O2 transport, which, in turn, is a function of blood flow and arterial O2 content, and hence SaO2. In nine patients with chronic obstructive airway disease the relationship between red cell mass and SaO2 was also determined and was found to be steeper than in the normal subjects (P < 0.05).