Background: Studies of space-flight anemia have uncovered a physiologic process, neocytolysis, by which young red blood cells are selectively hemolyzed, allowing rapid adaptation when red cell mass is excessive for a new environment. Objectives: 1)To confirm that neocytolysis occurs in another situation of acute plethora - when high-altitude dwellers with polycythemia descend to sea level; and 2) to clarify the role of erythropoietin suppression. Design: Prospective observational and interventional study. Setting: Cerro de Pasco (4380 m) and Lima (sea level), Peru. Participants: Nine volunteers with polycythemia. Interventions: Volunteers were transported to sea level; three received low-dose erythropoietin. Measurements: Changes in red cell mass, hematocrit, hemoglobin concentration, reticulocyte count, ferritin level, serum erythropoietin, and enrichment of administered 13C in heme. Results: In six participants, red cell mass decreased by 7% to 10% within a few days of descent; this decrease was mirrored by a rapid increase in serum ferritin level. Reticulocyte production did not decrease, a finding that establishes a hemolytic mechanism. 13C changes in circulating heme were consistent with hemolysis of young cells. Erythropoietin was suppressed, and administration of exogenous erythropoietin prevented the changes in red cell mass, serum ferritin level, and 13C-heme. Conclusions: Neocytolysis and the role of erythropoietin are confirmed in persons with polycythemia who descend from high altitude. This may have implications that extend beyond space and altitude medicine to renal disease and other situations of erythropoietin suppression, hemolysis, and polycythemia.