Pharmacological doses of estrogens induce osteosclerosis of the bone marrow, and depress colony-forming units (CFU's) and platelet and leukocyte counts in mice. A compensatoryincreasts in mice. A compensatory increase in splenic erythropoiesis prevents a fall in the hematocrit. The mechanism of this compensation was investigated as follows, BDF1 female mice were injected subcutaneously thrice weekly for 6 weeks wiht 50 mugg of estradiol benzoate (EB) or sesame oil (SO). Subsequently the hematocrit, red cell mass (RCM), and 4 hour per cent of 59Fe uptake into the femurs and spleens were determined in groups of five mice for 4 consecutive days. The RCM and hematocrit were not significantly different in the two groups. The per cent of 59Fe uptake into the femurs of EB-treated mice was less than 30 per cent of that in SO-treated mice and the per cent of 59Fe uptake into the spleens of EB mice was more than two times that in SO mice. To ascertain whether the increase in plenic erythropoiesis resulted from an increase in the number of splenic erythropoietin-responsive cells (ERC), the 4 hours per cent 59Fe uptake into the spleen was determined in continuously hypertransfused EB and SO mice injected with erythropoietin (Ep). Whereas hypertransfuction depressed the splenic per cent of 59Fe uptake in EB and SO mice equally, injection of Ep increased the per cent of 59Fe uptake into the spleens of of EB mice to greater than two times that of SO mice. Next, the plasma Ep level of mice injected with EB or SO for 2, 4, or 6 weeks was determined after exposure of the animals to hypoxia. Ep titers were greater than three times higher in EB mice than in SO mice, We conclude that at least two mechanisms act to cause the compensatory increase in splenic erythropoiesis after marrow suppression by EB: (1) the Ep levels rise and (2) the splenic ERC population increases. The latter is probably not due to the increased plasma Ep level because it also occurs in mice whose Ep production is suppressed by plethora.