Bronchiectasis guidelines regard treatment to prevent exacerbation and treatment of daily symptoms as separate objectives. We hypothesized that patients with greater symptoms would be at higher risk of exacerbations and therefore that a treatment aimed at reducing daily symptoms would also reduce exacerbations in highly symptomatic patients. Our study comprised an observational cohort of 333 patients from the East of Scotland (2012-2016). Either symptoms were modeled as a continuous variable or patients were classified as having high, moderate, or low symptom burden (>70, 40-70, and <40 using the St. George's Respiratory Questionnaire symptom score). The hypothesis that exacerbation reductions would only be evident in highly symptomatic patients was tested in a analysis of a randomized trial of inhaled dry powder mannitol (  = 461 patients). In the observational cohort, daily symptoms were a significant predictor of future exacerbations (rate ratio RR, 1.10; 95% confidence interval CI, 1.03-1.17;  = 0.005). Patients with higher symptom scores had higher exacerbation rates (RR, 1.74; 95% CI, 1.12-2.72;  = 0.01) over 12-month follow-up than those with lower symptoms. Inhaled mannitol treatment improved the time to first exacerbation (hazard ratio, 0.56; 95% CI, 0.40-0.77;  < 0.001), and the proportion of patients remaining exacerbation free for 12 months of treatment was higher in the mannitol group (32.7% vs. 14.6%; RR, 2.84; 95% CI, 1.40-5.76;  = 0.003), but only in highly symptomatic patients. In contrast, no benefit was evident in patients with lower symptom burden. Highly symptomatic patients have increased risk of exacerbations, and exacerbation benefit with inhaled mannitol was only evident in patients with high symptom burden.