The impending release of erythropoietin (EPO) is expected to result in a dramatic increase in hematocrit (Hct) for most hemodialysis (HD) patients. Our studies indicate that as Hct rises, dialyzer mass transport for some clinically critical solutes will be adversely affected. When whole blood clearances are corrected for solute-specific blood-water flows (QBH2O), the effect on the surrogate molecule, urea, used in urea kinetic modeling (UKM) is deceptively minimal, because only urea can diffuse almost instantly from red cells into blood water. For the critical solutes, potassium and phosphate, QBH2O is reduced to Q (plasma water). With a KoA of 690 ml/min at QB = 300, clearance of potassium falls at least 19.3% as Hct rises from 20 to 40% so that steady-state predialysis potassium could rise from 6.0 to 6.95 mEq/L. Already inadequate phosphate clearance falls at least 10% and additional loss results from physical interference by RBCs with solute diffusion. Hcts are further increased with rapid weight losses during high-efficiency dialyses (0.15 per 5% weight loss in 3 hours, r = 0.82) resulting in blood-side pressures such that most dialysis machines cannot provide adequate dialysate pressures to maintain low ultrafiltration rates (UFRs) at the high QB levels. The combination of pre-existing diffuse vascular disease, postdialysis hypovolemia, hypotension, decreased cardiac output, and increased blood viscosity has and will produce disastrous syndromes of organ ischemia, thrombosis, and infarction. Predialysis hypertension can worsen. Extreme caution and adjustment of dialysis regimen is necessary as patient Hct rises above 36%.