The processing of erythrocyte iron by the reticuloendothelial cell has been characterized by kinetic measurements of blood radioactivity made after the intravenous injection of heat-damaged erythrocytes labeled with (59)Fe and of transferrin-bound (55)Fe. The early reticuloendothelial release of iron, a matter of hours, was calculated from the plasma turnover rate of (55)Fe and the plasma reappearance of (59)Fe. Late release was calculated from the ratio of the cumulative incorporation of both tracers into the circulating red cell mass over a period of 2 wk. There was an initial processing period within the reticuloendothelial cell, after which radioiron either rapidly returned to circulation (t(1/2) 34 min) or was transferred to a slowly exchanging pool of storage iron within the reticuloendothelial cell (t(1/2) release to plasma of 7 days). These pathways were of equal magnitude in the normal dog. Reticuloendothelial release of iron was largely independent of the pre-existing plasma iron level or transferrin saturation. Diurnal fluctuations in the plasma iron level were shown to be the result of a variable partitioning of iron between the early and late release phases. Acute inflammation resulted in a prompt and marked increase in the fraction of iron stored (late phase), whereas depletion of iron stores resulted in a marked increase in early release.