Rationale: Cystic fibrosis (CF) is thought to be associated with mucus hypersecretion and thus the principal airway gel-forming mucins, MUC5AC and MUC5B, are also expected to be increased relative to non-CF secretions. However we have shown that these mucins are decreased during stable CF disease. Objectives: In this study we determine if these mucins increase during a pulmonary exacerbation of CF. Methods: Expectorated sputum was collected from 11 adults with CF during stable disease and then during a pulmonary exacerbation and from 12 healthy controls. MUC5AC and MUC5B proteins were measured by western blot. DNA content was measured using microfluorimetry. Results: MUC5AC protein increased by 908% and MUC5B by 59% (p < 0.05 for both) during an exacerbation compared with periods of stable disease. During stable disease, the v/v quantity of MUC5AC protein was 89% less than normal mucus and the mucin-associated sugars, measured using a lectin binding assay were 46% less compared to normal mucus. The concentration of DNA in CF sputum did not increase during an exacerbation. Conclusions: During a CF exacerbation, concentration of secreted mucin increased to the amount found in mucus from normal subjects suggesting that the capacity to secrete mucin in response to an infection or inflammatory stimulus is preserved in CF airways. This might help to protect the airway from injury.