In order to assess the effectiveness of cytapheresis as a possible alternative therapy for iron depletion, we performed a prospective study on eight unrelated patients with idiopathic hemochromatosis (HC). Isovolemic large-volume erythrocytapheresis (EA) (1000 ml apherisate) was carried out every four weeks until serum ferritin levels dropped below 300 micrograms/l (initial therapy). In all patients iron depletion was achieved after a mean of 8.5 months (8.9 EA with a total removal of 9.41 RBC). Serum ferritin levels decreased during initial therapy from 2596 +/- 399 to 168 +/- 83 ug/l. Serum iron level (240 +/- 35 to 125 +/- 48 ug/dl) and transferrin saturation (91 +/- 6 to 19 +/- 10%) declined accordingly. Clinical reexamination after initial therapy revealed improvement of clinical symptoms, normalization of hepatic iron, but liver histology remained unchanged. Reaccumulation of iron was prevented by maintenance EA therapy every five to six months (follow-up 18-36 months). Isovolemic large-volume EA is an effective, fast and safe method to remove excessive stored iron in patients with HC. Compared to phlebotomy, EA can selectively remove RBC, while saving plasma proteins, platelets, and clotting factors. Although, the need for special equipment and trained personnel as well as the relatively high costs are limiting factors of EA so far, it can be of crucial advance in some patients with HC.