Treatment with recombinant human erythropoietin (rHuEPO) successfully reverses anemia in uremic patients. Of major concern, however, are blood pressure increases during rHuEPO therapy, observed particularly in patients with a history of hypertension. The present study was designed to determine whether high-dose rHuEPO elevates blood pressure in nonuremic rats, and if so, whether preexisting hypertension enhances this response. We examined blood pressure responses to high (100 IU/kg) and very high (200 IU/kg) doses of rHuEPO or placebo, given subcutaneously every other day for 3 weeks to male spontaneously hypertensive rats (SHR) and their normotensive genetic controls (Wistar-Kyoto rats, WKY). The high and very high doses of rHuEPO stimulated equivalent increases in hematocrit, and this increase was always larger in SHR than in WKY. In contrast to the pattern of hematocrit changes, blood pressure did not change following high-dose rHuEPO but was elevated in both strains after the very high dose of the drug. Although the rise in blood pressure tended to be greater in SHR than in WKY, this difference was not significant. The data indicate that very high-dose rHuEPO raises blood pressure comparably in normotensive and hypertensive rats and this increase is relatively independent of the increase in hematocrit.