Painful piezogenic pedal papules were observed in 10 of 29 patients with Ehlers-Danlos syndrome. The diagnosis was made by examining each patient while he or she stood with full body weight on the heels and by observing the appearance of the painful papules on the medial, posterior, and lateral aspects of both heels. Biopsy specimens of papules demonstrated a thickened and dense dermis. The subcutaneous fibrous trabeculae were thin, with resultant poor compartmentalization of the fat. Painful piezogenic pedal papules are due to herniation of subcutaneous fat into the dermis, which is possibly due to structural defects of the connective tissue. The high prevalence of painful piezogenic pedal papules in our group of patients (34.5%) makes its direct association with the Ehlers-Danlos syndrome highly feasible, most probably because of the connective tissue defect that occurs in patients with Ehlers-Danlos syndrome.