It is a well-known fact that plasma substitutes reduce the number of platelets after one-time administration due to a dilution effect. So far, it has not been sufficiently investigated how a long-term hemodilution therapy affects platelet number, volume distribution and function. In 20 patients with cerebrovascular diseases a 10-day hemodilution therapy was carried out. The patients were randomly and double-blind treated with either medium molecular weight (MMW) hydroxyethyl starch (HES) 200/0.5 or low molecular weight (LMW) HES 40/0.5. On the first day of therapy, both groups showed a significant reduction in the number of platelets (-13.2% and -8.4%, respectively, p < 0.05), which was smaller than the dilution effect. During the course of the therapy, the platelet number increased, reaching its initial value. Mean platelet volume decreased in both groups significantly (MMW HES -4.7%, p < 0.05, LMW HES -4.6%, p < 0.01). The share of large platelets decreased disproportionately (MMW HES -15.4%, p < 0.01, LMW HES -11.4%, p < 0.01). Spontaneous platelet aggregation was not affected by HES. During the course of a long-term hemodilution therapy, the initial dilution-induced drop in platelet number is quickly compensated. The decline in mean platelet volume, which increases towards the end of the therapy, is due to a great extent to a decline in the number of large platelets. This in turn is probably caused by a colloid-osmotic shrinkage of the platelets and increased degradation. There were no signs for a clinically relevant impairment of platelet function.