We have previously shown that acute erythropoietic (Ep) stress by hemolysis or hypobaric hypoxia causes elevations in HbF in the baboon. The magnitude of these elevations is genetically determined, ranging from 3% to 60% (low, intermediate, and high responders). These genetic differences in HbF levels among animals are mainly due to differences in the number of HbF-containing cells ('F-cells'). The present study was undertaken to study the influence of prolongation and of the severity of Ep stress on HbF levels and the number of F-cells. The packed cells volume (PCV) of the blood of 4 animals, approximately 3 yr old, was maintained at 20% by daily phlebotomies, and the animals were exposed to varying degrees of hypobaric hypoxia for up to 40 days. In these experiments, the number of F-cells increased rapidly and reached individually constant levels ranging from 60% to 80%, when the PCV reached 20%, and no further increase was observed regardless of the subsequent degree of hypoxia. On the other hand, HbF levels, and with it the values for HbF per F-cell, increased proportionally to the severity of the Ep stress and could be maintained at a constant level depending on the degree of the hypoxia, e.g., at 19,000 feet HbF levels of one animal remained 20%-25% throughout the duration of the exposure of 14 days. These data are indicative of the separate control of F-cell numbers and of the levels of HbF per F-cell. It appears that with the increase of Ep stress, those Ep stem cells that have retained the HbF program are mobilized into maturation. A model, attempting to explain this phenomenon is presented.