Prior administration of a moderately hemolytic dose of 2-butoxyethanol (2-BE) in rats leads to autoprotection against the lethal effects of high doses. Digavalli and Mehendale (Arch. Toxicol. 69: 526-532;1995) showed that this autoprotection was due to recovery from the prior episode of hemolysis resulting in a higher proportion of young red blood cells (RBCs), which are more resilient to 2-BE. The objective of this research was to investigate the hypothesis that autoprotection can be entirely explained in terms of such changes in age composition of the RBC population. A simple simulation model was developed to provide predictions of the effect of various 2-BE dosage regimes, which were then experimentally verified. Some model predictions were confirmed by the experiments, but others were distinctly off the mark. The longer sequences (two or three successive episodes) in particular showed unexpected erythropoietic responses. This was further investigated in additional experiments, which also looked at reticulocyte counts and serum levels of erythropoietin (Epo). These showed that the release of reticulocytes following a 2-BE challenge is considerably faster than one would expect from the normal processing time in the bone marrow, and also becomes stronger at each successive challenge, resulting in remarkably high levels of reticulocytosis. It is concluded that changes in age composition of the RBCs cannot fully explain the time course of the hematocrit during consecutive administration of several doses of 2-BE, and that other mechanisms must play an important role as well. The results seem to indicate that after the hematocrit has recovered a buffer of (almost mature) reticulocytes remains available in the bone marrow for several days, which can be released almost immediately when another decrease in hematocrit is evoked.