Under carefully controlled conditions, seven aspirin-intolerant asthmatic patients were challenged with oral aspirin and experienced respiratory tract reactions with a decline in forced expiratory volume in 1 sec (FEV1) ranging from 26 to 64%. Venous blood samples, which were collected during the challenges, showed a rise in plasma histamine in all seven patients. The increase in plasma histamine occurred at the onset of their respiratory reactions and those patients with the most severe asthmatic responses were found to have the highest and most prolonged levels of plasma histamine. The aspirin-intolerant asthmatic patients were able to ingest Maalox or sodium salicylate without untoward effects, decline in FEV1 values or changes in plasma histamine levels. Ten non-asthmatic individuals and eight out of ten asthmatic control patients were able to ingest aspirin without any reactions or changes in their plasma histamine levels. However, two asthmatic control individuals, with severe asthma requiring treatment with moderate dosages of corticosteroids, were found to have elevated pre-challenge plasma histamine levels which increased during their ASA challenges despite the absence of respiratory reactions or changes in FEV1 values. It is possible that these two individuals were unsuspected aspirin-intolerant asthmatics. These studies demonstrate that asthmatic reactions to acetylsalicylates are associated with release of histamine into plasma in the subgroup of asthmatic patients with the aspirin-intolerance syndrome. Such a finding suggests that histamine may be one of the mediators of bronchospasm in aspirin-induced asthma.