<b><i>Background:</i></b> The recently published guidelines of the Spanish Society of Pulmonology and Thoracic Surgery encourage physicians to use outpatient antimicrobial therapy to treat exacerbations in patients with non-cystic fibrosis bronchiectasis (NCFB). The published literature on this topic, however, is scarce. <b><i>Methods:</i></b> We report a prospective observational cohort study of patients with NCFB who received treatment at home for at least one exacerbation episode between September 2012 and September 2017 as part of an outpatient parenteral antimicrobial therapy (OPAT) program. Patients were included in the analysis if they fulfilled all of the following criteria: established diagnosis of bronchiectasis according to current guidelines criteria, clinical exacerbation, requiring intravenous antibiotics because of failure to respond to oral antibiotics, or isolation of a microorganism resistant to oral options. <b><i>Objectives:</i></b> To evaluate the effectiveness and safety of the treatment of patients with NCFB exacerbations in an OPAT program under “real-world” conditions. <b><i>Results:</i></b> Sixty-seven patients were treated in the OPAT program due to bacterial exacerbations of NCFB. Forty-five (67.2%) patients were admitted to hospital for a median of 7 days before starting OPAT. Sixty-three (94%) patients achieved resolution of the exacerbation at the end of therapy. Four patients needed hospital readmission, and one died. The OPAT program saved 11,586 days of hospital admission, equivalent to EUR 7,866,904. <b><i>Conclusions:</i></b> OPAT appears to be a safe, effective, and efficient strategy for treating patients with exacerbations of NCFB.