Histamine released from dermal mast cells plays a central role in the increased vascular permeability in acute urticaria, and administration of anti-histamines usually suppresses development of wheals. Acute idiopathic urticaria, particularly a severe case, occasionally presents with acute inflammatory reactions such as low-grade fever and leukocytosis and is resistant to anti-histamines. Considering the wide spectrum of proinflammatory cytokines and chemokines that can be released from activated mast cells, some of them might be involved in the pathogenesis of urticaria. We measured plasma levels of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-alpha) in 16 cases of severe acute urticaria. None of them showed elevated plasma levels of IL-8 or TNF-alpha. Nine out of 16 acute urticaria patients showed elevated circulating IL-6 with concomitant increases in serum CRP levels. All such patients were resistant to conventional anti-histamine treatment and required systemic steroids for complete suppression of wheal development. After subsidence of the urticaria, their elevated IL-6 and CRP levels dropped to their normal ranges. In contrast, all but one patient without elevated circulating IL-6 was successfully treated with a H1 receptor antagonist, cetirizine. The data suggest involvement of IL-6 in the pathogenesis of severe acute urticaria that is resistant to anti-histamines.