We investigated 20 patients (12 men and 8 women) with end-stage renal disease sustained on hemodialysis to determine the effect of 6 weeks of increased dialysis dose on endogenous erythropoietin production. Increased dialysis dose was achieved by increasing thrice-weekly dialysis treatment time from 4 to 4.5 h and switching from an MCA 160 dialyzer to an F80 dialyzer. The mean age of the study subjects was 51 ± 13.8 years, and the mean duration of end-stage renal disease prior to the study was 31.4 ± 55.5 months. All subjects were receiving recombinant erythropoietin for at least 4 months prior to the study. The dialysis dose was increased from a mean reduction of urea of 60.7 to 72%. At baseline, the group’s mean hematocrit was 28.4 ± 3.4%, the mean predialysis endogenous erythropoietin level was 9.1 ± 4.5 (range 2.5–18.4) mU/ml, the mean reduction of urea was 60.7 ± 4%, and the mean transferrin saturation was 22.6 ± 15.5%. Mean thrice-weekly recombinant erythropoietin injections were administered intravenously after dialysis to each patient at a dose of 51 ± 19 U/kg body weight. After 6 weeks of an increased dialysis dose, the mean hematocrit increased from 28.4 ± 3.4 to 32.3 ± 3.3% (p = 0.0001), while the mean serum endogenous erythropoietin level decreased from 9.1 ± 4.5 (range 2.5–18.4) mU/ml to 6.1 ± 3.2 (range 2.5–13.4) mU/ml (p = 0.0001). We conclude that the serum endogenous erythropoietin levels decrease with increased dialysis dose and that the increase in hematocrit following increased dialysis dose is probably not mediated by changes in endogenous erythropoietin.