We have previously described a type I transforming growth factor (TGF)-β receptor (TβR-I) polymorphic allele, TβR-I(6A), that has a deletion of three alanines from a nine-alanine stretch. We observed a higher than expected number of TβR-I(6A) homozygotes among tumor and nontumor DNA from patients with a diagnosis of cancer. To test the hypothesis that TβR-I(6A) homozygosity is associated with cancer, we performed a case-control study in patients with a diagnosis of cancer and matched healthy individuals with no history of cancer and who were identical in their gender and their geographical and ethnic background to determine the relative germ-line frequencies of this allele. We found nine Tβ R-I(6A) homozygotes among 851 patients with cancer. In comparison, there were no TβR-I(6A) homozygotes among 735 healthy volunteers (P < 0.01). We also observed an excess of TβR-I(6A) heterozygotes in cancer cases compared to controls (14.6% versus 10.6%; P = 0.02, Fisher’s exact test). A subset analysis revealed that 4 of 112 patients with colorectal cancer were TβR-I(6A) homozygotes (P < 0.01). Using mink lung epithelial cell lines devoid of TβR-I, we established stably transfected TβR-I and TβR-I(6A) cell lines. We found that, compared to TβR-I, TβR-I(6A) was impaired as a mediator of TGF-β antiproliferative signals. We conclude that Tβ R-I(6A) acts as a tumor susceptibility allele that may contribute to the development of cancer, especially colon cancer, by means of reduced TGF-β-mediated growth inhibition.