Mannitol dry powder for inhalation has been developed for the treatment of patients with cystic fibrosis. Two randomized, double-blind, multinational, 26-week, phase III trials (CF-301 and CF-302) examined the efficacy of inhaled dry powder mannitol in patients aged ≥ 6 years with cystic fibrosis who were receiving standard care (with a substantial proportion of patients receiving dornase alfa and antibacterials at baseline). Good compliance was seen in both studies. A sustained, significant (p<0.001) improvement in forced expiratory volume in 1 second (FEV(1)) [mean absolute change from baseline over 26 weeks; primary endpoint] was seen in patients with cystic fibrosis who received inhaled mannitol, compared with the control group, in the CF-301 trial, but not in the CF-302 trial (p=0.059). In both CF-301 and CF-302, the relative increase from baseline in percent predicted FEV(1) and the improvement from baseline in forced vital capacity were significantly greater in patients receiving inhaled mannitol than in the control group. In a pooled analysis of the CF-301 and CF-302 trials, the relative risk of a pulmonary exacerbation requiring intravenous antibacterials was significantly reduced by 29% for inhaled mannitol recipients versus the control group (relative risk 0.71; 95% CI 0.51, 0.98) [p=0.039]. Inhaled dry powder mannitol was generally well tolerated in adults with cystic fibrosis in the CF-301 and CF-302 studies, with most treatment-emergent adverse events being of mild to moderate severity.