Abstract Rationale The principal underlying inhaled antibiotic treatment in bronchiectasis is that airway bacterial load drives inflammation, and therefore antibiotic treatment will reduce symptoms. Objectives To determine the relationship between bacterial load and clinical outcomes, assess the stability of bacterial load over time, and test the hypothesis that response to inhaled antibiotics would be predicted by baseline bacterial load. Methods We performed three studies. Studies 1 and 2 were prospective studies including adults with bronchiectasis. Study 3 was a post hoc analysis of a randomized trial of inhaled aztreonam. A priori patients were divided into low (<105 cfu/g), moderate (105–106 cfu/g), and high bacterial load (≥107 cfu/g) using quantitative sputum culture. Measurements and Main Results Bacterial load was a stable trait associated with worse quality of life and more airway inflammation in studies 1, 2, and 3. In study 3, patients with high bacterial load showed an improvement in the primary endpoint (Quality of Life–Bronchiectasis–Respiratory Symptoms Score at Week 4) in favor of aztreonam (mean difference of 9.7 points; 95% confidence interval, 3.4–16.0; P = 0.003). The proportion of patients who achieved an increase above the minimum clinically important difference was higher in the aztreonam group at Week 4 (63% vs. 37%; P = 0.01) and at Week 12 (62% vs. 38%; P = 0.01) only in high bacterial load patients. Conclusions Improvement of quality of life with inhaled aztreonam was only evident in patients with high bacterial load. Bacterial load may be a useful biomarker of severity of disease and treatment response.