Abstract (word count: 246) Rationale: A well-known clinical paradox is that severe bacterial infections persist in the lungs of cystic fibrosis (CF) patients despite the abundance of polymorphonuclear neutrophils (PMN) and the presence of high concentration of human neutrophil peptides (HNP), both of which are expected to kill the bacteria but fail to do so. The mechanisms remain unknown. Objectives: This study examined several possible mechanisms to understand this paradox. Method: PMN were isolated from sputum and blood of subjects with and without CF or non-CF bronchiectasis for phagocytic assays. HNP isolated from CF patients were used to stimulate healthy PMN followed by phagocytic tests. Measurements and Main Results: PMN isolated from the sputum of the bronchiectatic patients display defective phagocytosis that correlated with high concentrations of HNP in the lung. When healthy PMN were incubated with HNP, decreased phagocytic capacity was observed in association with depressed surface Fcγ RIII, actin-filament remodeling, enhanced intracellular Ca²⁺, and degranulation. Treatment of PMN with an intracellular Ca²⁺ blocker or α1-proteinase inhibitor to attenuate the activity of HNP largely prevented the HNP-induced phagocytic deficiency. Intratracheal instillation of HNP in Pallid mice (genetically deficient in α1-proteinase inhibitor) resulted in a greater PMN lung infiltration and phagocytic deficiency compared to wild type mice. Conclusions: HNP or PMN alone exert antimicrobial ability which was lost as a result of their interaction. These effects of HNP may help explain the clinical paradox seen in patients with inflammatory lung diseases, suggesting HNP as a novel target for clinical therapy.