Although some studies have clearly demonstrated tachyphylaxis to inhaled histamine in subjects with asthma, other studies have not. We speculated that histamine tachyphylaxis might be related to the degree of bronchial hyperreactivity (BHR) to histamine. We undertook three successive bronchial histamine challenges in two groups of 10 subjects with asthma chosen on the basis of their baseline BHR. In the group with mild asthma, the baseline provocative concentration of histamine causing a 20% fall in FEV1 (PC20) was greater than 2.5 mg/ml, and in the group with severe asthma, the baseline PC20 histamine was less than 1 mg/ml. The second and third histamine challenges in each subject were performed when FEV1 values had recovered to within 5% of the baseline FEV1 before the first challenge. There was no significant shift in reactivity to histamine from the first to the third challenge in either group. The geometric mean PC20 (+/- geometric SE) for the group with mild asthma was 4.27 (3.86 to 4.72) mg/ml for the first challenge and 5.42 (4.47 to 6.57) mg/ml for the third challenge. There was a mean increase of 0.34 doubling dilutions in PC20 for the group with mild asthma from the first to the third challenge, although this did not reach statistical significance. For the group with severe asthma, the geometric mean PC20 was 0.48 (0.39 to 0.59) mg/ml for the first challenge and 0.47 (0.38 to 0.59) mg/ml for the third challenge. There was no trend in this group toward any increase in PC20.(ABSTRACT TRUNCATED AT 250 WORDS)