To assess the role of histamine as a mediator in the response to exercise and isocapnic hyperventilation of cold air (IHCA) in asthma, we studied nine asthmatic subjects, age 13 to 25 years. All had exercise induced asthma (EIA) and positive responses to IHCA. Baseline lung function was measured before standardized challenges with histamine, exercise and IHCA. On separate days, these tests were repeated 3 h after a single oral dose of 120 mg terfenadine (TF). Histamine responsiveness decreased significantly, with a provocative concentration, producing a ± 20% fall in FEV1 (PC20), of 1.1 ± 0.8 mg/ml (mean ± SEM) before and 12.0 ± mg/ml after the antihistamine. EIA was significantly less after TF, with 53 ± 5% mean maximal falls in FEV1 from baseline before, and 29 ± 9% after treatment (P < 0.01, paired t-test). In contrast, the effect of TF on the response to IHCA was insignificant, with mean maximal falls of 45 ± 7% in FEV1 before, and 41 ± 7% after treatment. There was a correlation between PC20 and lowest FEV1 (% predicted) for EIA (r = 0.56, P < 0.05), but not for IHCA (r = 0.34, NS). This study indicates a role of histamine as a mediator in EIA but not in IHCA, supporting different mechanisms for both stimuli.