rHuEPO elevates hemoglobin concentration both by increasing red blood cell volume and by a decrease in plasma volume. This study delineates the association of rHuEPO-induced changes in blood volumes with changes in the renin-aldosterone system and renal function. 16 healthy males were given rHuEPO for 28 days in doses raising the hematocrit to 48.3 (4.1) %. Renal clearance studies with urine collections (N = 8) were done at baseline and at days 4, 11, 29, and 42. Glomerular filtration rate (GFR) was measured by (51)Cr-EDTA. Renal clearance of lithium (C(Li)) was used as an index of proximal tubular outflow and to assess segmental renal tubular handling of sodium and water. rHuEPO-induced increases in hematocrit occurred from day 10 onwards and was caused by both an increase in red cell volume and a fall in plasma volume. Well before that (from day 2 and throughout the treatment time), rHuEPO decreased plasma levels of renin and aldosterone (N = 8) by 21 - 33 % (P < 0.05) and 15 - 36 % (P < 0.05), respectively. After cessation of rHuEPO values returned to baseline. On days 11 and 29 C(Li) increased (P < 0.02) indicating a significant 10 - 16 % decrease in absolute proximal reabsorption of sodium and water (APR = GFR - C(Li), P < 0.05). GFR decreased slightly, albeit significantly on day 4 (P < 0.05). In conclusion, rHuEPO promptly, and before any changes in blood volumes and hematocrit can be detected, causes a down-regulation of the renin-aldosterone system. The results are compatible with a rHuEPO-induced reduction in proximal reabsorption rate leading to activation of the tubuloglomerular feedback mechanism and a fall in GFR. By this, treatment with rHuEPO may result in suppression of endogenous EPO synthesis secondary to a decrease in intrarenal oxygen consumption.