Background: Single measurements of peak oxygen uptake (V̇O2) have been shown to predict mortality in patients with cystic fibrosis (CF) although no longitudinal study of serial measurements has been reported in children. A study was undertaken to determine whether the initial, final, or the rate of fall of forced expiratory volume in 1 second (FEV1) or peak V̇O2 was a better predictor of mortality. Methods: Twenty eight children aged 8-17 years with CF performed annual pulmonary function and maximal exercise tests over a 5 year period to determine FEV1 and peak V̇O2, magnitude of their change over time, and survival over the subsequent 7-8 years. Analysis was done using Kaplan-Meier curves and Cox proportional hazard model. Results: Peak V̇O2 fell during the observation period in 70% of the patients, with a mean annual decline of 2.1 ml/min/kg. Initial peak V̇O2 was not predictive of mortality but rate of decline and final peak V̇O2 of the series were significant predictors. Patients with peak V̇O2 less than 32 ml/min/kg exhibited a dramatic increase in mortality, in contrast to those whose peak V̇O2 exceeded 45 ml/min/kg, none of whom died. The first, last, and rate of decline in FEV1 over time were all significant predictors of mortality. Conclusions: Higher peak V̇O2 is a marker for longer survival in CF patients.