BACKGROUND: Bronchiectasis guidelines are inconsistent with regard to the effectiveness of mucoactive agents, and their use varies geographically. Large trials are needed to assess safety and effectiveness. METHODS: For this open-label, randomized, two-by-two factorial trial at 20 sites in the United Kingdom, we enrolled participants with non-cystic fibrosis bronchiectasis who had frequent pulmonary exacerbations and daily sputum production. Current smokers and persons who had recently received mucoactive treatments were excluded. All participants received standard care and were also assigned either to one of three mucoactive-drug groups - hypertonic saline (the hypertonic-saline group), hypertonic saline and carbocisteine (the combination group), or carbocisteine (the carbocisteine group) - or to standard care alone. The comparisons were between hypertonic saline and no hypertonic saline and between carbocisteine and no carbocisteine, with each category consisting of two groups. The primary outcome was the number of pulmonary exacerbations over a 52-week period. Key secondary outcomes were scores on disease-specific health-related quality-of-life assessments, time to next pulmonary exacerbation, and safety. RESULTS: A total of 288 participants underwent randomization. No treatment interactions were found. The mean number of adjudicated fully qualifying pulmonary exacerbations over the 52-week period was 0.76 (95% confidence interval [CI], 0.58 to 0.95) with hypertonic saline as compared with 0.98 (95% CI, 0.78 to 1.19) with no hypertonic saline (adjusted between-group difference in the means, -0.25 [95% CI, -0.57 to 0.07; P = 0.12]) and 0.86 (95% CI, 0.66 to 1.06) with carbocisteine as compared with 0.90 (95% CI, 0.70 to 1.09) with no carbocisteine (adjusted between-group difference in the means, -0.04 [95% CI, -0.36 to 0.28; P = 0.81]). Secondary outcomes and the incidence of adverse events, including serious adverse events, were similar across the groups. CONCLUSIONS: In participants with bronchiectasis, neither hypertonic saline nor carbocisteine significantly reduced the mean incidence of pulmonary exacerbations over a period of 52 weeks. (Funded by the National Institute for Health and Care Research Health Technology Assessment Programme and others; ISRCTN Registry number, ISRCTN89040295.).