Background: Inhaled dry powder mannitol enhanced mucus clearance and improved quality of life over 2 weeks in non-cystic fibrosis bronchiectasis. This study's objective was to investigate the efficacy and safety of dry powder mannitol over 12 weeks. Methods: Patients with bronchiectasis confirmed by high-resolution CT (HRCT) scan, aged 15 to 80 years, with FEV1 ≥ 50% predicted and ≥ 1 L participated in a randomized, placebo-controlled, double-blind study. Patients with a negative mannitol provocation test were randomized to inhale 320 mg mannitol (n = 231) or placebo (n = 112) bid for 12 weeks. To further assess safety, the same mannitol dose/frequency was administered to a patient subset in an open-label extension over 52 weeks. Primary end points were changes from baseline at 12 weeks in 24-h sputum weight and St. George's Respiratory Questionnaire (SGRQ) score. Results: There was a significant difference of 4.3 g in terms of change in sputum weight over 12 weeks (95% CI, 1.64-7.00; P = .002) between mannitol and placebo; however, this was largely driven by a decrease in sputum weight in the placebo group. This was associated, in turn, with more antibiotic use in the placebo group (50 of 112 [45%]) than in the inhaled mannitol group (85 of 231 [37%]). There was no statistical difference between the groups (P = .304) in total SGRQ score (mannitol, -3.4 points [95% CI, -4.81 to -1.94] vs placebo, -2.1 points [95% CI, -4.12 to -0.09]). In a subgroup study (n = 82), patients receiving mannitol showed less small airway mucus plugging on HRCT scan at 12 weeks compared with patients receiving placebo (P = .048). Compliance rates were high, and mannitol was well tolerated with adverse events similar to those of placebo. Conclusion: Because the difference in sputum weights appears to be associated with increased antibiotic use in the placebo group, a larger controlled study is now required to investigate the long-term mannitol effect on pulmonary exacerbations and antibiotic use.