In anemic non-renal and hemodialysis (HD) patients, erythropoietin (EPO) levels vary > 10 fold at any hematocrit (Hct), suggesting marked variation in endogenous EPO production among individuals. We hypothesized that this intrinsic variation that reflects differences in bone marrow sensitivity to circulating EPO could account for the > 10 fold variability in recombinant human erythropoietin (rHuEPO) requirements of HD patients to correct their anemia, and could be evaluated by examining the response to blood loss and measurement of red blood cell (RBC) survival (tau). The renal response to blood loss was studied in normal patients (N = 14) and in non-rHuEPO treated HD (n = 12) patients by measuring the increase in EPO (delta EPO) above basal level. Serum samples were obtained before and after the blood loss event. Delta EPO after a one-unit phlebotomy was larger in normal patients than in HD patients, although delta Hct was larger in HD. Regression of delta EPO against Hct/erythropoietin basal level, an index of bone marrow sensitivity, indicated parallel responses in normal and HD subjects, with the magnitude of response decreased in HD. To exclude an effect of a difference in RBC survival between control and end-stage renal disease (ESRD) patients, we measured more than 16 other patients (Hct 24.1) that averaged 107 days (range 70-140) and were independent of Kt/V (mean 1.01; range 0.67-1.38). Intersubject differences in bone marrow sensitivity to EPO exist and are detected by delta EPO after blood loss. Response of delta EPO to blood loss is diminished, but not abrogated, by renal disease.