Protein depletion in rats is associated with hemoconcentration, diminution of red cell mass, and suppression of erythropoiesis. In a rat model, repletion with standard diets or total parenteral nutrition was associated with gain in body weight and regeneration of red cell mass. Hematocrit values did not reflect the degree of red cell mass diminution associated with protein depletion. Intravenous repletion of normal and protein-depleted rats, unlike oral refed cohorts, was associated with elevated 2,3 diphosphoglycerate (DPG) values and a ‘relative anemia.’ It is postulated that elevated red cell 2,3 DPG lowers the hypoxie stimulus for erythropoietin production by enhancing oxygen unloading to the tissues, thus partially compensating for the anemia associated with total parenteral nutrition.