An increased level of airway responsiveness has been proposed as a risk factor associated with the onset and prognosis of chronic airway obstruction. To determine this, longitudinal studies are necessary, with measurement of both the level of airway responsiveness and of additional risk factors, such as cigarette smoking, made before measurement of pulmonary function decline. The association of airways responsiveness with decline in FEV1 has been prospectively studied in a random sample of the Dutch population. Longitudinal data from 921 males, providing 2,376 paired observations, and 698 females, providing 1,682 paired observations, were used for analysis. Differences between responders and nonresponders (PC10 < or = 16 mg/ml of histamine) were estimated from linear regression analyses stratified by gender and smoking status, with adjustment for age, residential area, the presence of respiratory symptoms, indicators for each interval, and residuals of FEV1 at the beginning of the interval. Responders had a greater mean yearly decline in FEV1, and the differences between responders and nonresponders were similar for all gender and smoking subgroups. In an overall regression model, subjects with airway hyperresponsiveness had a significantly steeper decline in FEV1, independent of the other variables (males: beta = -12.5 ml/yr, SEM = 3.22, p < 0.001; females: beta = -11.50 ml/yr, SEM = 2.98, p < 0.001). The current analyses conclusively demonstrated that increased airway responsiveness is an independent risk factor for an accelerated decline in FEV1 and, hence, for the development of chronic obstructive lung disease. The mechanisms by which increased airway responsiveness leads to an accelerated decline in FEV, are imperfectly understood and require further study.