To assess the effect of recombinant human erythropoietin (EPO) on the factors regulating blood pressure (BP), we determined the hemoglobin level (Hgb), blood viscosity (BV), plasma renin activity (PRA), plasma concentrations of aldosterone (PAC), adrenaline (Ad), noradrenaline (NAd), and atrial natriuretic peptide (ANP), and serum and intracellular concentrations of cations before and after 3 months of EPO treatment (40units/kg/week of EPO intravenously after each hemodialysis session) in 11 patients undergoing maintenance hemodialysis. Intracellular sodium concentration ([Na⁺]_i) was measured using erythrocytes with flame photometry. EPO treatment was associated with significant increases in Hgb (7.1±1.4 to 8.4±1.8g/dl, p<0.01), mean BP (103±11.4 to 116±19.9mmHg, p<0.01), [Na⁺]_i (4.99± 0.78 to 6.22±0.96mmol/l, p<0.01) and BV (1.39±0.14 to 1.53±0.18 c.p., p<0.05), but no significant alteration in PRA, PAC, Ad, NAd, ANP, or in the serum concentration of Na⁺, K⁺, and Ca²⁺. The changes in mean BP (ΔMBP) were significantly correlated with Δ[Na⁺]_i (R=0.676, p=0.022) and ΔBV (R=0.668, p=0.034), but not with ΔHgb. By multiple regression analysis, Δ[Na⁺]_i and ΔBV independently contributed to ΔMBP; ΔMBP=2.27×Δ[Na⁺]_i+32.2×ΔBV+3.37 (R=0.695). These data suggest that intracellular sodium accumulation as well as increased blood viscosity may be independently involved in the blood pressure elevation after EPO treatment in patients under maintenance hemodialysis. We found no evidence supporting a role of circulating hormonal factors, such as the renin-angiotensin system, adrenaline, or ANP, in the change in blood pressure. (Hypertens Res 1996; 19: 91-95)