BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by progressive lung function decline, commonly measured by forced expiratory volume in one second (FEV). Uncovering the genetic basis of FEV decline is essential for understanding COPD pathophysiology and for developing therapies. We hypothesized that gene expression patterns in inflammatory pathways are associated with FEV decline. METHODS: We analyzed whole blood RNA-sequencing data from the 5 (n = 4,147) and 10 year visits (n = 435) in the COPDGene Study. Gene expression was assessed in three analyses: cross-sectional associations with FEV at two separate time points, association between year 5 gene expression and FEV changes from year 5-10, and longitudinal changes in both gene expression and FEV. A gene signature derived from the 5-year visit was linked to FEV decline across three intervals (baseline to 5 years, 5 to 10 years, and baseline to 10 years) and tested for validation in the ECLIPSE study. RESULTS: Distinct gene sets emerged in the three analyses (Cross-sectional: 961 genes; FEV Change: 179; Longitudinal: 532). Only two genes ( and ) overlapped across all analyses, while unique genes (e.g., , and ) were context-specific. Pathway analysis of genes from the longitudinal analysis highlighted oxidative stress and immune processes. A 20-gene signature was derived, including 17 genes positively and three negatively associated with FEV. These signatures were significantly associated with FEV-related traits in COPDGene and ECLIPSE. CONCLUSIONS: These findings reveal molecular markers of FEV decline, offering insights into COPD pathophysiology and potential therapeutic targets.