Clinical heterogeneity in bronchiectasis remains a challenge to improve the appropriate targeting of therapies and patient management. Antimicrobial peptides (AMPs) have been linked to disease severity and phenotype.Can we identify clusters of patients based on the levels of AMPs, airway inflammation, tissue remodeling and damage; and to establish their relationship with disease severity and clinical outcomes?A prospective cohort of n=128 stable patients with bronchiectasis were recruited across three centers in three different countries (Spain, Scotland and Italy). Two-step cluster strategy was used to stratify patients according to levels of lactoferrin, lysozyme, LL-37 and SLPI in sputum. Measurements of inflammation (IL-8, TGF-β and IL-6), tissue remodeling and damage (GAGs, MMP-9, neutrophil elastase, total and bacterial DNA) and neutrophil chemotaxis were assessed.Three clusters of patients were defined according to distinct airway profiles of AMPs. They represented groups of patients with gradually distinct airway infection and disease severity. Each cluster was associated with an airway profile of inflammation, tissue remodeling and damage. The relationships between soluble mediators were also distinct between clusters. This analysis allowed the identification of the cluster with the most deregulated local innate immune response. During follow-up, each cluster showed different risk of suffering three or more exacerbations (p=0.03) and different time to first exacerbation (p=0.03).Bronchiectasis patients can be stratified in different clusters according to profiles of airway AMPs, inflammation, tissue remodeling and damage. The combination of these immunological variables shows a relationship with disease severity and future risk of exacerbations.