The effect of long-term hemodialysis in 58 nonanemic end-stage renal disease patients treated with recombinant human erythropoietin (r-HuEPO; EPOGEN [epoetin alfa], AMGEN Inc, Thousand Oaks, CA) has been examined in detail. Increased dialyzer prescription (Kt/V) was correlated with the need for a lower maintenance dose of r-HuEPO. After 1 year of therapy, stable increases in hemoglobin, hematocrit, and reticulocyte levels were obtained without other clinically significant hematologic changes. In a randomly selected subgroup of 14 patients, 5 developed predialysis increased diastolic pressures. In this group, an early increase in cardiac output and ejection fraction was accompanied by a decrease in total peripheral resistance index (TPRI). Later changes showed a steady increase in TPRI with an associated mild increase in mean arterial pressure. A slight increase in cardiac responsiveness to fistula occlusive maneuvers was also found. Hospital admissions and mortality rates were not significantly different from those of a cohort control population. At a fixed Kt/V there were slight decreases in solute clearances with correction of anemia, with phosphate, urate, and creatinine changing significantly. Corrective measures required simple compensatory adjustments in dialysis blood-flow rates. Intradialytic complications were noticeably improved. Patients receiving long-term r-HuEPO replacement therapy do remarkably well without major complications.