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Objective: A long-standing hypothesis is that a low ratio of airway caliber to lung size is associated with bronchial hyperresponsiveness (BHR). The aim of our study was to measure the association between airway caliber relative to lung size (expressed as the ratio between forced expiratory flow, midexpiratory phase, divided by forced vital capacity [FEF(25%-75%)/FVC]) and BHR measured by a methacholine challenge test, adjusting for age, height, sex, smoking history, geographic area, respiratory symptoms, and baseline forced expiratory volume in 1 second (FEV1)., Material and Methods: We carried out a multicenter cross-sectional study of the general Spanish population in 2647 subjects from the European Community Respiratory Health Survey (ECRHS I). The ECRHS questionnaire was administered, total and specific immunoglobulin E were measured, and skin tests, spirometry, and a methacholine challenge test were performed., Results: We show the relationship of the various clinical and sociodemographic variables with the 2 parameters indicative of a positive methacholine test. The lower the FEF(25%-75%)/FVC ratio was, the greater the risk of HRB, after adjustment for variables (odds ratio [OR]=0.09; 95% confidence interval [CI], 0.04-0.018 for the concentration provoking a 20% decrease in FEV1, and OR=0.06; 95% CI, 0.03-0.12 for the dose provoking a 20% decrease in FEV1)., Conclusions: There is a significant association between the FEF(25%-75%)/FVC ratio and BHR after adjustment for age, atopy, smoking, geographic area, respiratory symptoms, and initial FEV1.