The identification of connective tissue disease (CTD) in patients with bronchiectasis (BE) is crucial due to increased risk of mortality and hospitalization in CTD associated BE (CTD-BE), particularly in rheumatoid arthritis (RA). To explore prevalence and characteristics of CTD-BE, consecutive adults with clinically and radiologically significant BE were enrolled in a prospective, observational study at the Policlinico Hospital in Milan, Italy, and underwent blood test for antinuclear antibodies (ANA), extractable nuclear antigens antibodies (ENA), anti-neutrophil cytoplasm antibodies (ANCA) and anti-citrullinated protein antibodies (ACPA) at BE diagnosis during stable state. All patients with at least one positive test underwent a rheumatologic evaluation to reach a diagnosis of CTD. Among 468 (median age: 63 years [IQR 48-71], 78.2% female) patients, 147 (31.4%) had at least one positive antibody, including ANA (25.9%), ENA (3.2%), ANCA (3.8%) and ACPA (4.7%). A final diagnosis of CTD was performed in 26 patients (5.6%), including RA (2.5%), Sjogren's syndrome (0.6%) and vasculitis (0.6%). Age was significantly lower in idiopathic BE (median age: 62 years in idiopathic BE; median age: 70 years in CTD-BE; p < 0.001) while no differences in sex, bronchiectasis severity index (BSI), number of exacerbations, chronic infection due to any pathogen and Pseudomonas aeruginosa, were seen between the groups. These data support recommendations by guidelines that autoimmune screening should be individualized and prescribed only in patients with coexisting clinical features of arthritis, connective tissue disease and/or systemic vasculitis.