Because of the important role of peripheral airways inflammation in the pathogenesis of asthma and COPD and because of the known anti-inflammatory actions of corticosteroids, we hypothesized that endogenous cortisol may influence the rate of decline of pulmonary function with aging. We examined the basal plasma cortisol concentration and serial spirometric measurements of 86 healthy men participating in the Normative Aging Study. Subjects selected for this study were free of any chronic illnesses and denied chronic use of any medications. Blood for cortisol determination was obtained with the subject in the supine position at 8:00 A.M. Two consecutive spirometric examinations that took place an average of 4.7 yr apart were employed in the analysis. Cross-sectional analysis revealed a weak (p = 0.08) direct relationship between the basal plasma cortisol concentration and FEV1. The cortisol concentration and FVC appeared unrelated. Longitudinal analysis revealed a significant (p = 0.008) relationship between the plasma cortisol concentration and the rate of decline of FEV1 over the follow-up interval after adjustment for age, height, smoking status, and initial FEV1 in a multivariate regression model. This multivariate model predicts that subjects with cortisol concentration 1 standard deviation (23.3 ng/ml) below the mean would experience FEV1 decline 71.6 ml/yr greater than subjects with cortisol concentration 1 standard deviation above the mean. This difference was comparable to the estimated 69.5 ml/yr difference between current and never smokers. Cortisol concentration was unrelated to the rate of decline of FVC. The data suggest that physiologic concentrations of cortisol may modulate the process responsible for the deterioration of ventilatory function with aging.