STUDY OBJECTIVE The ratio between forced expiratory flow between 25% and 75% of vital capacity (FEF(25-75)) and FVC is thought to reflect dysanapsis between airway size and lung size. A low FEF(25-75)/FVC ratio is associated with airway responsiveness to methacholine in middle-aged and older men. The current study was designed to assess this relationship in both male and female subjects over a broader range of ages. STUDY DESIGN Data analysis of consecutive subjects who had a >or= 20% reduction in FEV(1) after <or= 189 cumulative units of methacholine over a 7-year period. SETTING Pulmonary function laboratory in a university-affiliated hospital. PATIENTS A total of 764 consecutive subjects aged 4 to 91 years (mean +/- SD age, 40.8 +/- 19.6 years). There were 223 male (29.3%) and 540 female (70.7%) subjects. MEASUREMENTS AND RESULTS Airway reactivity was assessed as the dose-response slope of the reduction in FEV(1) from baseline vs the cumulative dose of inhaled methacholine. The cumulative dose of methacholine causing 20% reduction in FEV(1) (PD(20)) was used as the indicator of airway sensitivity. In a linear regression model that included age, height, and percentage of predicted FEV(1), the FEF(25-75)/FVC ratio accounted for 7.6% of variability in airway reactivity (p < 0.0001, r(2) = 0.076). Subjects with higher airway sensitivity, indicated by lower PD(20), also had a lower FEF(25-75)/FVC ratio. CONCLUSIONS A low FEF(25-75)/FVC ratio, indicating small airway size relative to lung size, is associated with higher airway sensitivity and reactivity to methacholine in susceptible subjects.