A comparative crossover study of intravenously (i.v.) and subcutaneously (s.c.) administered recombinant human erythropoietin (r-HuEPO) was conducted in 20 patients with end-stage renal disease on maintenance hemodialysis. The patients were randomized into two groups. Group 1 received r-HuEPO i.v. thrice weekly and group II r-HuEPO s.c. twice weekly for 12 weeks, then the therapy was crossed over for another 12-week period. The initial dose was 50 U/kg/i.v. dose and 40 U/kg/s.c. dose. In all but 1 patient an adequate hematologic response was obtained. In group 1 the mean hemoglobin (Hb) level increased from 4.8 (Hbo) to 6.0 after 12 weeks (HbΠ) and further to 6.5 mmol/l after 24 weeks (Hb24) throughout the study (0.025 < p < 0.05). In group II it increased from 4.6 (Hb₀) to 7.1 (Hbι2) to 6.9 mmol/l (Hb24) (0.01 < p < 0.025). There was a significant difference between the two groups (p < 0.05). The rise in Hb in group II during the first 12 weeks of the study was achieved by only half the cumulative dose of r-HuEPO (11,820 U) per kilogram compared to the consumption in group I (24,575 U). In the last 12 weeks of the study the requirement of r-HuEPO to maintain Hb level was equal in the two groups. In group I serum erythropoietin (EPO) level increased slowly throughout the study. In group II an increment was followed by a decrease beyond prestudy level. This happened at an erythropoietic response with mean hematocrit (Hct) about 35%. In group I a mean Hct > 35% was never reached. This might indicate the existence of an EPO-Hct feedback mechanism. In conclusion, s.c. administration is significantly more effective than i.v. administration as induction therapy, requiring only half the dose of r-HuEPO. Also it can be administered twice weekly, and a start dose of 40 U/kg/dose is suggested aiming at a Hct not exceeding 35%.