BACKGROUND: Fibroblast activation protein-α (FAP-α), which is a serine protease specially expressed on the surface of the cancer stromal cells, plays an important role in the progression and prognosis in diverse malignancies. However, the role of FAP-α in non-small cell lung cancer (NSCLC) is still unknown. MATERIALS AND METHODS: We enrolled 59 NSCLC patients who received complete resection. Sections of paraffin-embedded primary NSCLC specimens of all the patients were stained with antibody directed against FAP-α. Overall, percentage (Grade 0-3) and intensity (0-3+) of stromal FAP-α staining of the tumor were assessed. RESULTS: FAP-α was detected in >76 % of the specimens examined, and its high expression seemed to be correlated with poor tumor differentiation (P = 0.06). Furthermore, both increased FAP-α staining percentage and intensity were associated with worse overall survival of the patients (percentage, P = 0.0087; intensity, P = 0.05). Higher FAP-α staining percentage was observed in those patients with increased peripheral neutrophil and lymphocyte count ratio (P = 0.034). CONCLUSIONS: FAP-α is highly expressed in cancer stroma and also a predictor of poor survival of NSCLC patients. Elevated FAP-α expression may be associated with inflammation and suppressed lymphocyte-dependent immune response, which then result in the tumor progression. Therefore, FAP-α plays an important role in the progression of NSCLC, and its high expression is a predictor of poor survival. Targeting FAP-α may be a novel strategy for NSCLC therapy.