Hydroxyethyl starch (HES) is widely used as a plasma substitute. Serious side effects occur only rarely, whereas a high incidence of severe pruritus has been reported. Moreover, tissue storage of HES has been demonstrated in various organs. The aim of the current study has been to examine precisely the intracellular uptake and long-term storage of HES in the skin. Skin biopsies from 119 patients who received HES of various preparations and cumulative dosage were obtained 30 min to 130 months after infusion therapy. The samples were analysed by ultrastructural and immunoelectron microscopy with HES-specific monoclonal and polyclonal antibodies. A characteristic vacuolisation of perivascular histiocytes was a regular finding in all skin biopsies as early as 1 day after a single infusion of 30 g. Immunoreactivity for HES was demonstrable within the vacuoles. Generally, the size and number of vacuoles in the histiocytes increased concomitantly with the cumulative dosage. Following administration of higher HES dosages, vacuoles were demonstrable in endothelial cells of blood and lymphatic vessels, basal keratinocytes, epithelia of sweat glands and in small peripheral nerves, the last mentioned being associated with pruritus. A subsequent reduction of the vacuoles in size and number could be demonstrated within 52 months. In nerves, HES deposits persisted no longer than 17 months paralleling the cessation of pruritus. Biopsies taken after 94 months exhibited no HES deposits in the skin. The condensation and final dissolution of the vacuoles may either indicate the release and subsequent redistribution of HES into the circulation or lysosomal degradation.