The normal relationship between red cell mass measured, with (51)chromium-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 O(2) tension was found only over the lower half of the range of O(2) tensions where Sa(O2) was also decreased (r = - 0.7731, P < 0.005). This suggested that O(2) saturation rather than tension is the more important determinant of the erythropoietic response to chronic hypoxia. If this response is regulated by tissue O(2) tension, then it will be influenced by O(2) transport, which, in turn, is a function of blood flow and arterial O(2) 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).