Transforming growth factor beta (TGFbeta) is known to exert both positive and negative effects on different stages of tumor formation. Of the TGFbetaisoforms, TGFbeta1 is highly expressed in prostate cancer and leads to tumor promotion and metastasis. Increased expression of TGFbeta1 is associated with more aggressive tumors and poor prognosis. Several polymorphisms in TGFB1 have been identified, and two variants in strong linkage disequilibrium, C-509T and T+29C, show increased serum levels. Because of the potential role of TGFB1 variants in prostate cancer and progression, we hypothesized that these two TGFB1 variants would be associated with prostate cancer risk, particularly later, more aggressive stage tumors. To test this, we conducted a nested case-control study of 492 men diagnosed with prostate cancer from the Physicians Health Study and 492 age-matched controls. In this study, cases who were homozygous for the T allele at position -509 had a 2.4-fold increased risk of more advanced stage of prostate cancer [95% confidence interval (95% CI) 1.03-5.43; P = 0.04]. The T allele frequencies in cases and controls were 32.7% and 31.4%, respectively. The same polymorphism showed a 1.23 nonsignificant odds ratio (OR) for overall prostate cancer risk (95% CI 0.80-1.87). Cases who were homozygous for the C allele at position +29 did not show any significant increase in risk for either total prostate cancer (OR 1.19, 95% CI 0.82-1.74) or advanced stage prostate cancer (OR 1.33, 95% CI 0.66-2.68). The C allele frequency in cases and controls were 39.9% and 38.5%, respectively. Our data suggest that the TGFB1 C-509T variant that affects expression of TGFbeta1 may play a role in advanced stage prostate cancer.