Three children with classical Ehlers-Danlos syndrome were studied. Electron microscopic observation of the skin demonstrated a hyaluronic acid-dominant glycosaminoglycan structure in the intercellular matrix. Biochemical analysis showed a significant increase in hyaluronic acid content, as compared with the skin of sex- and age-matched children, including a non-affected brother of a patient. In addition, enhanced hyaluronic acid synthesis was demonstrated in vitro, using a patient's dermal fibroblasts. Analysis of the collagen showed no apparent abnormalities.