Rationale: Circulating leukocyte RNA transcripts are systemic markers of inflammation, which have not been studied in CF lung disease. While the standard assessment of pulmonary treatment response is FEV₁, a measure of airflow limitation, the lack of systemic markers to reflect changes in lung inflammation critically limits testing proposed therapeutics. Objectives: We sought to prospectively identify and validate peripheral blood leukocyte genes that could mark resolution of pulmonary infection and inflammation, utilizing a model by which RNA transcripts could increase the predictive value of spirometry. Methods and main results: Peripheral blood mononuclear cells (PBMCs) were isolated from 10 CF patients with acute pulmonary exacerbations before and after therapy. RNA expression profiling revealed 10 genes significantly changed with treatment, with comparison to matched non-CF and stable CF controls to establish baseline transcript abundance. PBMC RNA transcripts were prospectively validated, utilizing real time-PCR amplification, in an independent cohort of acutely ill CF patients (n=14). Patients who responded to therapy were analyzed by general estimating equations and multiple logistic regression, such that changes in FEV₁% predicted were regressed with transcript changes. Three genes, CD64, ADAM9, and CD36, were significant and independent predictors of therapeutic response, beyond FEV₁alone (p<0.05). In both cohorts, receiver operating characteristic (ROC) analysis revealed greater accuracy when genes were combined with FEV₁. Conclusions: Circulating mononuclear cell transcripts characterize response to treatment of pulmonary exacerbations. Even in small patient cohorts, changes ingene expression in conjunction with FEV₁, may enhance current outcomes measures for treatment response.