Erythromelalgia is a rare disorder characterized by burning pain of the extremities associated with red discoloration and increased temperature of the skin. We observed the effects of several drugs on two patients with primary erythromelalgia. Anti-inflammatory drugs such as aspirin had no effects for their symptoms. The alpha-adrenergic agonist midodrine slightly reduced skin temperature and redness of the extremities, and minimally reduced the pain in one patient. The partial alpha-adrenergic agonist and 5-hydroxytryptamine (5-HT) agonist/antagonist dihydroergotamine transiently reduced skin temperature and pain to some degree in one patient. The 5-HT and histamine antagonist cyproheptadine effectively relieved the burning pain and increased skin temperature.