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Background. Idiopathic pulmonary fibrosis (IPF) is a progressive disease for which two antifibrotic drugs recently were approved. However, an unmet need exists to predict responses to antifibrotic treatment, such as pirfenidone. Recent data suggest that upregulated expression of CXCR4 is indicative of outcomes in IPF. Research Question. Can quantitative, molecular imaging of pulmonary CXCR4 expression as a biomarker for disease activity predict response to the targeted treatment pirfenidone and prognosis in patients with IPF? Study Design and Methods. CXCR4 expression was analyzed by immunohistochemistry examination of lung tissues and reverse-transcriptase polymerase chain reaction analysis of BAL. PET-CT scanning with the specific CXCR4 ligand 68Ga-pentixafor was performed in 28 IPF patients and compared with baseline clinical characteristics. In 16 patients, a follow-up scan was obtained 6 to 12 weeks after initiation of treatment with pirfenidone. Patients were followed up in our outpatient clinic for > 12 month. Results. Immunohistochemistry analysis showed high CXCR4 staining of epithelial cells and macrophages in areas with vast fibrotic remodeling. Targeted PET scanning revealed CXCR4 upregulation in fibrotic areas of the lungs, particularly in zones with subpleural honeycombing. Baseline CXCR4 signal demonstrated a significant correlation with Gender Age Physiology stage (r = 0.44; P = .02) and with high-resolution CT scan score (r = 0.38; P = .04). Early changes in CXCR4 signal after initiation of pirfenidone treatment correlated with the long-term course of FVC after 12 months (r = −0.75; P = .0008). Moreover, patients with a high pulmonary CXCR4 signal on follow-up PET scan after 6 weeks into treatment demonstrated a statistically significant worse outcome at 12 months (P = .002). In multiple regression analysis, pulmonary CXCR4 signal on follow-up PET scan emerged as the only independent predictor of long-term outcome (P = .0226). Interpretation. CXCR4-targeted PET imaging identified disease activity and predicted outcome of IPF patients treated with pirfenidone. It may serve as a future biomarker for personalized guidance of antifibrotic treatment.