Indoor particulate matter (PM2.5) exposure may contribute to systemic inflammation in adults with cystic fibrosis (CF), who already experience chronic airway inflammation and impaired mucociliary clearance. This study evaluated indoor PM2.5 exposure and cytokine activation in 22 adults with CF living in rural New England. Participants underwent five days of continuous and integrated PM monitoring, plasma cytokine profiling, symptom assessment, and home-activity logging. Higher proportions of time spent in elevated PM2.5 exposure zones were significantly associated with increased circulating pro-inflammatory cytokines, including IL-17A, IL-8, IL-7, TGF-α, PDGF-AA/BB, and TNF-β, consistent with neutrophil-driven inflammation and tissue remodeling. Eotaxin decreased with greater PM exposure, suggesting a shift away from eosinophilic pathways. These findings support a link between indoor air quality and immune activation in CF and highlight the importance of environmental exposures in disease burden. Future work should incorporate seasonal monitoring, larger cohorts, and targeted interventions such as HEPA filtration.