High-flow nasal therapy (HFNT) provides several pathophysiological benefits in chronic respiratory disorders. We aimed to evaluate the effectiveness of long-term HFNT in patients with bronchiectasis (BE). Methods: This is a retrospective bicentric case-control study of outpatients with BE on optimized medical treatment with a severe exacerbation requiring hospitalization in the previous year. Patients on long-term home HFNT (cases) and patients on optimized medical treatment alone (controls) were matched by age, sex, bronchiectasis severity index, and exacerbations in the previous year. Data on BE exacerbations, hospitalizations/year, mucus features, respiratory symptoms, and pulmonary function were collected. The primary outcome was the change from baseline in the exacerbation rates at 12 months between groups. Results: 20 patients in the HFNT group and 20 controls were included. A significant reduction in exacerbations [−1.9 (−2.8 to −0.9), p = 0.0005] and hospitalizations [−0.7 (−1.1 to −0.3), p = 0.0006] was found in the HFNT group vs controls. A slight improvement in pulmonary function [FEV1% +6,1% (+1% to +11.3%) (p = 0.0219), FVC% +4.6% (+0.8% to +8.3%) (p = 0.0188) and FEF25–75% +13.4 (+11 to +15.9) (p = 0.0189) was also found in the HFNT group compared to controls. Conclusions: In this preliminary study, long-term domiciliary HFNT improved the clinical course of patients with BE.