After infusion therapy with hydroxyethyl starch (HES) on account of sudden hearing loss, a 68-year-old woman developed a marked and persistent periocular swelling. This extraordinary adverse effect caused us to search for an explanation by means of histopathology, immunohistochemistry, immunoelectron microscopy and biochemistry. In lesional periocular skin and in normal-appearing skin, lysosomal storage of HES could be detected with a specific HES antibody in histiocytes, endothelial cells, basal keratinocytes and small nerves. In the periocular skin, a stronger deposition of HES was found in addition to distinct xanthomatous changes as well as features of lymphoedema. In view of lysosomal HES storage we measured the pH-dependent activity of the lysosomal α-glucosidase (GAA) in cultured fibroblasts. We found a 50% decreased activity of the acid GAA, which is consistent with a heterozygous state of glycogenosis type II (Pompe's disease) and potentially of pathogenetic relevance for the intralysosomal accumulation of HES. Xanthomatous changes and lymphoedema are likely to be secondary effects, but contribute considerably to the clinical manifestation of persistent visible swelling. This observation could point to a role for GAA in the elimination of tissue-stored HES. Patients with decreased activities of GAA may be at risk of unusual adverse effects following extraordinary and prolonged tissue storage of HES, especially if it is infused in large quantities.