Rationale: Chronic obstructive pulmonary disease (COPD) is heterogeneous. We hypothesized that COPD subgroups defined by both genetic risk (polygenic risk score, PRS) and blood gene expression (transcriptional risk score, TRS) would differ in disease severities, activities, and risk for progression. Methods: We created two PRS and three TRS groups in a training set [n=1,374 non-Hispanic white (NHW) COPDGene participants], which we characterized using STRING protein-protein interaction network analyses. We applied Enrichr drug repurposing analyses and multivariable regressions to test group associations with COPD-related outcomes, adjusting for confounders. We examined these six omics-defined groups in non-overlapping test sets [n=1,133 NHW COPDGene, n=468 ECLIPSE]. Results: Two groups differed substantially, defining ?high disease activity? and ?severe disease risk? subtypes. ?High disease activity? participants had low PRS/high TRS, accelerated prospective FEV1 decline (COPDGene: -51 mL/year; ECLIPSE: -40 mL/year), and altered MMP12, TGF-?, and IL-16 biology. ?Severe disease risk? participants had high PRS/high TRS, lower spirometry, greater emphysema and airway thickness, and changes in IL-20 and TNF signaling. Both subtypes had lower mean BMI than other subtypes, with altered growth hormone, leptin, and prolactin levels. ?High disease activity? individuals were enriched in gene sets perturbed by treatment with fibrates, calcium channel blockers, and antithyroid medications, and ?severe disease risk? individuals by treatment with 5-lipoxygenase and angiotensin-converting enzyme inhibitors. Conclusions: PRS and TRS identified subtypes with distinct clinical and biological features.