Background: Non-cystic fibrosis bronchiectasis (BE) is a chronic lung disease characterized by permanent dilatation of airways with chronic infection and inflammation that leads to frequent infectious exacerbations. There is a lack of information about the burden of multidrug resistant (MDR) pathogens in BE exacerbations. Objectives: We aimed to investigate risk factors associated with isolation of MDR pathogens in BE exacerbations. Methods: A prospective observational study of patients with diagnosis of BE and recruited in two tertiary-care hospitals. Demographic data, comorbid conditions prognostic scales, prior treatments, number of exacerbations in the previous year and microorganisms isolated during exacerbation were recorded. MDR were defined according to European Centre for Disease Prevention and Control (ECDC) when non-susceptibility to at least one agent in three or more antimicrobial categories depending on the type of microorganism. The first exacerbation requiring antibiotic treatment or hospital admission for every patient was included. Results: We included 233 exacerbations and microorganisms were isolated in 159 episodes. MDR pathogens were found in 20.1% episodes: 16 P. aeruginosa (48.5%), 6 MARSA (18.2%) and 2 Extended spectrum betalactamase + Enterobacteria (6.1%), and they appeared more frequently in hospitalized patients (24.5% vs. 10.2%). Three independent MDR risk factors were found: chronic renal disease (Odds ratio (OR), 7.60), hospitalization in the previous year (OR, 3.88) and prior MDR isolation (OR, 5.58). Conclusions: Hospitalization in the previous year, chronic renal disease, and prior MDR isolation are risk factors for MDR pathogens in exacerbations.