Most healthy subjects challenged with cotton bract extract demonstrate some degree of bronchospasm. This response has been associated with the endogenous production of histamine by the inhalation of cotton bract extract. We examined whether this responsiveness reflects increased sensitivity to histamine. Thirty-one healthy subjects were screened for sensitivity to cotton bract extract administered by nebulization. Pulmonary function was measured using partial expiratory flow-volume curves on which flows at 60% of the control vital capacity below total lung capacity were measured (MEF40%(P)). Responders were defined as subjects who exhibited a 20% or greater decrease in MEF40%(P) after 10 min inhaling cotton bract extract. Of those screened, 10 subjects were responders. From the remaining nonresponders, 11 consecutive subjects were selected. The maximal decrease in MEF40%(P) in responders was 40.5 +/- 5.1%, compared to 10.9 +/- 2.2% in nonresponders. The dose-response relationship for histamine was measured in all subjects, using inhalations of progressively more concentrated histamine solutions. The mean +/- SEM threshold for the responders was 38.4 +/- 7.4 mg of histamine per ml, compared to 42.2 +/- 6.8 mg of histamine per ml for responders (difference not significant). The percentage decrease in MEF40%(P) at the threshold dose was 27.6 +/- 3.7% for responders and 32.4 +/- 5.2% for nonresponders (difference not significant). We conclude that healthy subjects sensitive to cotton bract extract do not exhibit increased reactivity to histamine. This suggests that responders are not, in general, subclinical asthmatics, and that the difference between responders and nonresponders to CBE is not due to increased histamine sensitivity among responders.