A subgroup of patients with interstitial lung disease (ILD) have a degenerative phenotype known as progressive pulmonary fibrosis (PPF) irrespective of etiology, which is seen in roughly 30% of ILD cases. Anti-fibrotic medications slow progression of PPF, thus highlighting the need to reliably predict future progression when it is still preventable. The objective of this study was to examine whether whole blood gene expression profiles could predict a progressive phenotype in ILD patients. Whole blood RNA-seq samples of a retrospective cohort of treatment-naïve ILD patients were analyzed for differentially expressed genes (DEGs). After adjusting for sex and baseline predicted forced vital capacity (FVC%), we identified 17 DEGs (FDR<0.25) in association with FVC% slope over 6 months (n=42), including PGAM1P8, TSPAN33, and LRFN4 (FDRs = 0.01, 0.19, 0.20), which were also significantly associated with FVC% slope over 12 months (n=63). When examining FVC% slope over 24 months (n=68), we identified 70 DEGs including FMOD, PCSK6, TGFB1I1, and VEGFC (FDRs = 0.18, 0.18, 0.25, 0.25), all of which have previously been associated with fibrotic processes in ILDs. Using a linear mixed effects model to examine the effect of baseline gene expression on FVC% trajectory, we identified 1 gene (lnc-COL4A1-1) that was significantly associated with FVC% decline at 6, 12, and 24 months (FDRs = 0.02, 0.06, 0.14). Taken together, these data suggest that blood expression of genes associated with fibrosis are associated with long-term decline in FVC%, while genes associated with immune activation (TSPAN33 for B-cells and LRFN4 for monocytes) may precede short-term declines in FVC%.