Purpose: Whole blood donation leads to a well-defined pronounced loss of erythrocytes and thrombocytes. In contrast, plasma pheresis techniques separate almost exclusively plasma without explicit cell loss of blood donors. Methods: 39 healthy first time whole-blood (FTWB) donors, 44 healthy permanent whole-blood (WB) donors and 32 healthy permanent plasma (PLP) donors (plasma pheresis) between 20 and 40 years (mean age 31 ± 6 years, gender matched) were included in the study. In predonation blood samples sTPO and sEPO levels were determined by a commercially available enzyme-linked immunosorbent assay (R&D Systems). Results: In FTWB donors sEPO and sTPO levels were within a normal range (8.7 ± 2.6 mU/ml and 62.5 ± 39.4 pg/ml). Whole-blood donation caused a significant increase in sEPO to 13.2 ± 6.8 mU/ml (p < 0.001), and in PLP donors a tendency to elevated sEPO levels (10.7 ± 4.7 mU/ml, p < 0.076) could be observed. In contrast, sTPO remained unaffected in regular PLP donors and in WB donors. Conclusions: Altered serum concentrations of erythropoietin may represent regulatory physiological effects to compensate the loss of erythrocytes by stimulation of bone marrow production.