The potential role of neutrophil elastase in exacerbating pulmonary infection and tissue damage in cystic fibrosis (CF) has led to proposals for treatment of lung disease in CF with the elastase inhibitor, α1-proteinase inhibitor (α1PI). Reports that α1PI is inactivated in the CF lung suggest that the effectiveness of α1PI therapy depends on the quantity of elastase present and the extent of α1PI inactivation, both of which are expected to vary with disease severity. In this study we assessed the elastase-α1PI profile in sputum and plasma from CF patients with various degrees of pulmonary involvement. Levels of active elastase in sputum samples increased with severity of pulmonary disease (F ratio = 5.63, p < 0.01), as did sputum levels of α1PI (F ratio = 4.88, p < 0.01). A positive correlation was observed between sputum levels of active elastase and α1PI (r = 0.68, p < 0.005). Plasma α1PI levels were also elevated in CF patients compared with control subjects (p < 0.005), indicating a compensatory increase in plasma and sputum levels of α1PI in response to increased elastase load. Molar levels of total immunogenic neutrophil elastase were, on average, 12 times higher than α1PI in CF sputum. These results suggest that the major contributor to the elevated levels of active elastase observed in the CF lung is an increase in elastase release rather than inactivation of α1PI.