Rationale: In adults with cystic fibrosis (CF), Pseudomonas aeruginosa (PA) is the most common sputum pathogen and increasingly multidrug-resistant (MDR). To address this problem, we identified a novel approach leveraging the antibacterial properties of lytic bacteriophages (phages) to design personalized phage therapy. Lytic phages are bacteria-specific viruses that self-amplify while killing bacteria. We are investigating mechanisms for lipopolysaccharide (LPS) targeting phage to not only kill MDR PA but also reduce lung inflammation by suppressing LPS production in surviving PA mutants. Methods: 8 subjects with MDR PA were treated with inhaled phage targeting LPS via FDA-approved emergency IND request and IRB approval. Phage was administered daily (outpatient) or twice (inpatient) daily for 7-10 days. Sputum and spirometry were obtained pre- and post-phage therapy. Sputum was processed to measure PA load and metagenomics. PA isolates were cultured from sputum to steady-state and supernatants collected. LPS was extracted from the supernatants and quantified. Human airway epithelial cells, CFTR mutant (CFBE41o-) and wildtype (16HBEo-), were stimulated with pre- and post-phage PA supernatants and analyzed for EGFR phosphorylation (EGFR-p), IL-6 and IL-8 production. Results: Compared to pre-phage, sputum PA titers post-phage therapy were significantly decreased (2.2±0.76 log reduction, p<0.05). In addition, post-phage therapy LPS concentration (EU/mL), decreased 34.1% ± 4.5% (p<0.05). After phage therapy, precent predicted FEV1 (ppFEV1) increased 0%-8.9%; pre [day -30 to -1] and post [day 21 to 35] (p<0.01). Analysis of airway epithelial cell experiments for epidermal growth factor receptor activation (EGFR-p) and cytokine production are ongoing. Conclusions: MDR PA is increasingly common in CF and exceedingly difficult to manage. Therefore, development of novel therapeutic approaches that reduce infection with minimal side-effects, are highly desirable to the CF community. LPS phage therapy offers a unique opportunity to investigate targeting a bacteria virulence factor in the human lung. Phage therapy decreases PA titers and LPS concentration and improves ppFEV1. LPS has been shown to cause lung inflammation and injury. One mechanism for this is epidermal growth factor receptor (EGFR) activation inducing cytokine and mucin production. Ongoing experiments are investigating the potential for LPS phage therapy to decrease airway and lung inflammation. These results highlight the potential to carefully design phage therapy to provide anti-infective and anti-inflammatory benefits.