Introduction: We hypothesized that plasma transforming growth factor-beta 1 (TGF-beta 1) level and its dynamic change are correlated with the prognosis of locally advanced non-small cell lung cancer (NSCLC) treated with radiation therapy (RT). Methods: Patients with stage IIIA or IIIB NSCLC treated with RT with or without chemotherapy were eligible for this study. Platelet poor plasma was collected from each patient within 1 week before RT (pre-RT) and at the 4th week during RT (during-RT). TGF-beta 1 level was measured with enzyme-linked immunosorbent assay. The primary end point was overall survival (OS) and the secondary end point was progression-free survival (PFS). Kaplan-Meier and Cox regression were used for risk factor evaluation. Results: A total of 65 patients were eligible for the study. The median OS and PFS were 17.7 and 13.7 months, respectively. In univariate analysis, performance status, weight loss, radiation dose, and TGF-beta 1 ratio (during-RT/pre-RT TGF-beta 1 level) were all significantly correlated with OS. In the multivariate analysis, performance status, radiation dose, and TGF-beta 1 ratio were still significantly correlated with OS. The median OS was 30.7 months for patients with TGF-beta 1 ratio <= 1 versus 13.3 months for those with TGF-beta 1 ratio more than 1 (p = 0.0029); and the median PFS was 16.8 months versus 7.2 months, respectively (p = 0.010). Conclusions: In locally advanced NSCLC, the decrease of TGF-beta 1 level during RT is correlated with favorable prognosis.