Purpose: Transforming growth factor (TGF)-beta 1 signaling is involved in cancer-cell metastasis. We investigated whether single nucleotide polymorphisms (SNPs) at TGF beta 1 were associated with overall survival (OS) and distant metastasis-free survival (DMFS) in patients with non-small cell lung cancer (NSCLC) treated with definitive radiotherapy, with or without chemotherapy. Methods: We genotyped TGF beta 1 SNPs at rs1800469 (C-509T), rs1800471 (G915C), and rs1982073 (T+29C) by polymerase chain reaction-restriction fragment length polymorphism in blood samples from 205 NSCLC patients who had had definitive radiotherapy at one institution in November 1998-January 2005. We also tested whether the TGF-beta 1 rs1982073 (T+29C) SNP affected the migration and invasion of A549 and PC9 lung cancer cells. Results: Median follow-up time for all patients was 17 months (range, 1-97 months; 39 months for patients alive at the time of analysis). Multivariate analysis showed that the TGF beta 1 rs1800469 CT/CC genotype was associated with poor OS (hazard ratio [HR] = 1.463 [95% confidence interval {CI} = 1.012-2.114], P = 0.043) and shorter DMFS (HR = 1.601 [95% CI = 1.042-2.459], P=0.032) and that the TGF beta 1 rs1982073 CT/CC genotype predicted poor DMFS (HR = 1.589 [95% CI = 1.009-2.502], P = 0.046) and poor brain MFS (HR = 2.567 [95% CI = 1.155-5.702], P = 0.021) after adjustment for age, sex, race, performance status, smoking status, tumor histology and volume, stage, receipt of concurrent radiochemotherapy, number of chemotherapy cycles, and radiation dose. Transfection with TGF beta 1+29C (vs. +29T) stimulated the migration and invasion of A549 and PC9 cells, suggesting that TGF beta 1+29C may be linked with increased metastatic potential. Conclusions: TGF beta 1 genotypes at rs1800469 and rs1982073 could be useful for predicting DMFS among patients with NSCLC treated with definitive radiation therapy. These findings require validation in larger prospective trials and thorough mechanistic studies.