Patients may complain of pain at the injection site after subcutaneous (s.c.) administration of erythropoietin (EPO).Local pain due to s.c.EPO into the thigh was evaluated in 60 hemodialysis patients in a double-blind, placebo-controlled study.Identical volumes and concentrations (2000 IU in 0.5 ml) of phosphate-buffered epoetin-alpha (EPO-αph), citrate-buffered epoetin-alpha (EPO-αci) and epoetin-beta (EPO-β) were compared to 0.5 ml of 0.9% saline (SAL), used as placebo.The patients received the 4 injections at thesame occasion.For pain evaluation, a verbal scale ranging from no pain (0) to extremely painful (5) and a 10 cm ungraduated visual analogue score (VAS) (0 =no pain, 10 =maximal pain) were used.Treatment acceptance was assessed (yes/no) and expressed as apercentage of the population.Ranking of the preparations from 1 to.4 according to increasing local discomfort was performed.Median verbal pain scores and interquanile ranges were 1.0(0-2) for SAL,.0.0 (0-2) for EPO-β, 1.5 (0-3) for EPO-αph (p ≤0.05 vs SAL and EPO-β)and 3.0 (2-4) for EPO-αci (p ≤0.001 vs EPO-αph).VAS was 0.9 (0.5-2.5) for SAL, 0.9 (0.4-2.4) for EPO-β, 2.7 (0.8-5.7) for EPO-αph (p ≤0.001 vs SAL and EPO-β) and 4.2 (1.7-6.4) for EPO-αci (p ≤0.001 vs EPO-αph).Treatment acceptance was 73% for SAL, 78% for EPO-β, 60% for EPOαph (p ≤0.05 vs EPO-β) and 32% for EPO-αci (p ≤0.05 vs EPO-αph).Ranking was.2 (1-3)for SAL, 2 (1-2) for EPO-β, 3 (1-4) for EPO-αph (p ≤0.05 vs SAL and EPO-β) and 4 (3-4) for EPO-αci (p ≤0.05 vs SAL and EPO-β) and 4 (3-4) for EPO-αci (p ≤0.001 vs EPO-αph).In conclusion, s.c.EPO-αph is better accepted than s.c.EPO-αci.However, s.c.EPO-β is less painful.