A defective prostaglandin metabolism in patients with erythromelalgia may explain several of the clinical features of this condition, such as the red discoloration and burning sensations of the skin. In two patients with erythromelalgia a grossly abnormal bullous reaction to intradermally injected PGE1, PGE2, and PGF1alpha occurred, whereas a normal reaction appeared after injection of histamine, serotonin, and bradykinin. Furthermore, prostaglandin-like material was detected in increased concentration in skin perfusates from these patient. In PGE1-equivalents the concentration amounted to 2.0 and 3.2 ng/ml of the original perfusate, as compared to 0.1 ng/ml in normal skin. The capacity of synthesizing prostaglandins was increased in skin biopsy material from both patients. At least part of the therapeutic effect of aspirin in these patients may be due to the influence of this drug on prostaglandin metabolism.