Transforming growth factor-beta (TGF-beta) inhibits the proliferation of carcinomas in early stages of breast cancer, whereas it promotes tumor growth and metastasis in later stages of cancer. We evaluated a possible association between TGF-beta1 gene polymorphisms and breast cancer risk in a population-based case-control study of Chinese women living in Shanghai, which included 1,127 breast cancer cases and 1,228 population controls. Two polymorphisms, C-509T and T+29C, were in strong linkage disequilibrium. There were no overall differences in the genotype distribution of T+29C polymorphisms of the TGF-beta1 gene among cases and controls. However, the distribution of the high-activity C allele of T+29C polymorphisms differed by cancer stages (P(trend) = 0.02). This allele was associated with decreased risk of early-stage breast cancer [stages 0 and I; odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.54-0.99], and the OR was further reduced to 0.66 (95% CI, 0.45-0.96) for those homozygous for this allele (P(trend) = 0.03). On the other hand, the same allele was associated with nonsignificantly increased risk of breast cancer with advanced stages III and IV (OR, 1.33; 95% CI, 0.81-2.18), which differed significantly from that observed for early-stage cancer (P = 0.04). This result suggests a possible dual effect of TGF-beta1 shown by in vitro experiments and provides an explanation for some of the inconsistent findings from previous epidemiologic studies that did not evaluate this association by cancer stage.