BACKGROUND: The transforming growth factor-beta (TGF-beta) signaling pathway is involved in many aspects of tumorigenesis, including angiogenesis and metastasis. The authors evaluated this pathway in association with survival after a diagnosis of colon or rectal cancer. METHODS: The study included 1553 patients with colon cancer and 754 patients with rectal cancer who had incident first primary disease and were followed for a minimum of 7 years after diagnosis. Genetic variations were evaluated in the genes TGF-beta1 (2 single nucleotide polymorphisms [SNPs]), TGF-beta receptor 1 (TGF-betaR1) (3 SNPs), smooth muscle actin/mothers against decapentaplegic homolog 1 (Smad1) (5 SNPs), Smad2 (4 SNPs), Smad3 (37 SNPs), Smad4 (2 SNPs), Smad7 (11 SNPs), bone morphogenetic protein 1 (BMP1) (11 SNPs), BMP2 (5 SNPs), BMP4 (3 SNPs), bone morphogenetic protein receptor 1A (BMPR1A) (9 SNPs), BMPR1B (21 SNPs), BMPR2 (11 SNPs), growth differentiation factor 10 (GDF10) (7 SNPs), Runt-related transcription factor 1 (RUNX1) (40 SNPs), RUNX2 (19 SNPs), RUNX3 (9 SNPs), eukaryotic translation initiation factor 4E (eiF4E) (3 SNPs), eukaryotic translation initiation factor 4E-binding protein 3 (eiF4EBP2) (2 SNPs), eiF4EBP3 (2 SNPs), and mitogen-activated protein kinase 1 (MAPK1) (6 SNPs). RESULTS: After adjusting for American Joint Committee on Cancer stage and tumor molecular phenotype, 12 genes and 18 SNPs were associated with survival in patients with colon cancer, and 7 genes and 15 tagSNPs were associated with survival after a diagnosis of rectal cancer. A summary score based on ‘at-risk’ genotypes revealed a hazard rate ratio of 5.10 (95% confidence interval, 2.56-10.15) for the group with the greatest number of ‘at-risk’ genotypes; for rectal cancer, the hazard rate ratio was 6.03 (95% confidence interval, 2.83-12.75). CONCLUSIONS: The current findings suggest that the presence of several higher risk alleles in the TGF-beta signaling pathway increase the likelihood of dying after a diagnosis of colon or rectal cancer.