Rationale: C-X-C motif chemokine 13 (CXCL13) mediates B-cell trafficking and is increased, proportionately to disease activity, in many antibody-mediated syndromes. Dysregulated B-cells have recently been implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis. Objective: To determine if CXCL13 is associated with IPF progression. Methods: CXCL13 was measured in lungs by DNA microarray and immunohistochemistry, and in plasma by ELISA. Measurements and Main Results: CXCL13 mRNA was 3-fold and 8-fold greater in IPF lungs (n=92) compared to COPD (n=191) and normal (n=108) specimens, respectively (p<0.0001). IPF lungs also showed increased CXCL13 staining. Plasma CXCL13 concentrations (pg/ml) were greater in 95 IPF patients (94±8) than in 128 COPD subjects (53±9) and 57 normals (35±3) (p<0.0001). Circulating CXCL13 levels were highest in IPF patients with pulmonary artery hypertension (p=0.01) or acute exacerbations (p=0.002). Six-month survival of IPF patients in the highest quartile of plasma CXCL13 was 65±10% vs. 93±10 in the others (HR=5.5, 95%CI:1.8-16.9, p=0.0008). CXCL13 increases by >50% in IPF serial assays, irrespective of initial values, also presaged respiratory failure (HR=7.2, 95%CI=1.3-40.0, p=0.008). In contrast, CXCL13-clinical associations in COPD subjects were limited to modest correlations with FEV1 (p=0.05) and progression of radiographic emphysema (p=0.05). Conclusions: CXCL13 is increased, and a prognostic biomarker in IPF patients, and more so than in COPD patients. This contrast indicates CXCL13 over-expressions are intrinsic to IPF, rather than an epiphenomenon of lung injury. The present data implicate CXCL13 and B-cells in IPF pathogenesis, and support considerations for trials of specific B-cell-targeted therapies in patients with this intractable disease.