The potential stimulating effect of erythropoietin on the production of fetal proteins (FPs) has not been explored in human subjects. Therefore, the plasma levels of fetal fibrinogen (FF), carcinoembriogenic antigen (CEA), alpha-fetoprotein (AFP), and fetal hemoglobin (HbF) were measured in 12 uremic hemodialyzed patients before the first administration and after 1, 2, and 3 months of low-dose erythropoietin (r-Hu-EPO; 45 U/kg body wt I.V., thrice weekly). Such a treatment efficaciously increased total hemoglobin (Hb). CEA and AFP increased from 5.8 +/- 1.1 ng/ml and 2.9 +/- 0.9 ng/ml to the final value of 43.2 +/- 3.9 ng/ml and 8.7 +/- 1.1 ng/ml, respectively, in the absence of detectable neoplastic diseases. The levels of FF did not change. HbF levels increased from <3% of Hb to the peak value of 48% at the end of the first month; subsequently, a progressive reduction in HbF was observed. Similar changes were detected in the reticulocyte count (RET). A striking correlation was found between HbF and RET (r = 0.8633, p < 0.0001), indicating that the increment in HbF was dependent on the erythroid activity. In conclusion, this study evidences broader than expected effects of erythropoietin on the synthesis of FP and suggests that (1) r-Hu-EPO markedly increases HbF in a condition of suppressed bone marrow activity, (2) the measurement of the cell proliferation markers CEA and AFP is unreliable during r-Hu-EPO therapy, and (3) the prothrombotic state associated with chronic r-Hu-EPO treatment in patients with uremia cannot be attributed to the presence of FF.