Pulmonary function and nutritional status are important determinants of exercise capacity in patients with cystic fibrosis (CF). Studies investigating the effects of determinants, such as genotype or infection and inflammation, are scarce and have never been analysed in a multivariate longitudinal model. A prospective longitudinal cohort study was performed to evaluate whether genotype, chronic inflammation and infection were associated with changes in exercise capacity. Furthermore, we investigated whether exercise capacity can predict clinical outcome. 504 exercise tests of 149 adolescents with CF were evaluated. Maximal oxygen uptake corrected for body mass % predicted declined 20% during adolescence, and was associated with immunoglobulin (Ig)G levels and chronic Pseudomonas aeruginosa infection. A lower exercise capacity was associated with a higher mortality, steeper decline in pulmonary function and greater increase in IgG levels. Since a decline in exercise capacity during adolescence was negatively associated with IgG levels and chronic P. aeruginosa infection, these data emphasise the importance of prevention and treatment of chronic inflammation and infections in patients with CF. Furthermore, a lower exercise capacity was associated with a higher mortality rate, steeper decline in pulmonary function and higher increase in IgG levels with increasing age in adolescents with CF. This stresses the value of regular exercise testing for assessing prognosis in adolescents with CF.