The total-body red blood cell mass (RBCM) decreases during the first few days of spaceflight; however, the pathophysiology of "spaceflight anemia" noted on return to earth is poorly understood. In studies before, during, and after a 9-day mission we determined the rates of removal and replacement of RBCs by using chromium 51. The rate and efficiency of RBC production were assessed with iron 59. Serial measurements were made of plasma volume (PV), RBCM, serum ferritin level, and erythropoietin level. PV decreased within hours, resulting in an increased total body hematocrit during the first few days of the mission. Serum erythropoietin level decreased within 24 hours and remained low. Circulating RBCs disappeared at a normal rate during flight, but few new cells replaced those destroyed, resulting in a decrease in RBCM of 11% during the mission. After 22 hours in space, intramedullary formation of cells continued at near preflight levels as measured by erythron iron turnover. The coexistence of new cell formation in the bone marrow and failure of cells to be released into the blood is consistent with ineffective erythropoiesis. Microgravity causes blood located in gravity-dependent spaces to shift to a central volume. We conclude that the initial adaptation is a reduction in PV resulting in plethora. Increase in total body hematocrit causes a decrease in erythropoietin production. RBCM decreases because RBCs destroyed at a normal rate are not replaced.(ABSTRACT TRUNCATED AT 250 WORDS)