The normal relationship between red cell mass measured, with ⁵¹chromium-labeled red cells, and arterial oxygen saturation (Sa_O2) 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 Sa_O2 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 Sa_O2 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 Sa_O2. In nine patients with chronic obstructive airway disease the relationship between red cell mass and Sa_O2 was also determined and was found to be steeper than in the normal subjects (P < 0.05).