Most severe pulmonary exacerbations (PExs) in adult patients with cystic fibrosis (CF) are treated with 2 week of intravenous (IV) antibiotics. At occasions, the treatment is extended. The morbidity and the cost of extending the treatment are considerable. Risk factors and the outcome of extending the course of treatment have not been formally investigated. This was a prospective study. Decision to extend the course of antibiotics was made in patients who were not deemed to have responded to the initial 14 days of treatment. Risk factors examined for extending the course were site of treatment (home or hospital), CF symptom score, body mass index (BMI), forced expiratory volume in the first second (FEV1) and C-reactive protein (CRP) at days 1 and 14 of the treatment. The following outcome measures were assessed for PExs requiring prolongation of treatment: FEV1, BMI, CF symptom score, CRP and number of days until the following PExs. PExs that were treated with 14 day course were used for comparison. Of all the PExs, 22.9% needed extension of treatment beyond day 14. Compared with PExs needing 14 days of antibiotics, CF symptom score, FEV1 and CRP at day 14 were worse in those who had to have the course extended. Extending the course of IV antibiotics to 21 days improved symptom score, but not any of the other outcome measures, including the number of days until the next PEx. Extending the course beyond 21 days did not result in improvement in any outcome measure. PExs in patients with worse lung disease and greater residual symptoms and lung inflammation at day 14 of antibiotic treatment were associated with the extension of the course of IV antibiotics. Prolonging the treatment to 21 days improved symptoms, but did not result in improvement in any other short-term or lung outcome measures.