Increased colorectal epithelial cell proliferation is an early, common event in colorectal carcinogenesis. We conducted a pilot, colonoscopy-based case-control study (n = 49 cases, 154 controls) of incident, sporadic colorectal adenoma to investigate endogenous cell growth factors and receptor, as well as the balance of growth factors, as potential modifiable pre-neoplastic biomarkers of risk for colorectal neoplasms. We measured transforming growth factor alpha (TGFα), TGFβ(1), and TGFβ receptor II (TGFβRII) expression in normal-appearing mucosa from the rectum, sigmoid colon, and ascending colon using automated immunohistochemistry and quantitative image analysis. Diet and lifestyle were assessed via questionnaires. The mean ratio of rectal TGFα to TGFβ(1) expression and mean rectal TGFα expression were, respectively, 110% (P = 0.02) and 49% (P = 0.04) higher in cases than in controls, and associated with a more than two-fold (OR 2.42, 95% CI 0.85-6.87) and a 62% (OR 1.62, 95% CI 0.63-4.19) higher risk of colorectal adenoma. TGFβ(1) and TGFβRII expression were 6.7% (P = 0.75) and 7.2% (P = 0.49), respectively, lower in cases than in controls. The TGFα/TGFβ(1) expression ratio was 105% higher among smokers than among non-smokers (P = 0.03). These preliminary data suggest that the balance of TGFα and TGFβ(1) expression, and to a lesser extend TGFα alone, in the normal-appearing rectal mucosa may be directly associated with risk for incident, sporadic colorectal neoplasms, as well as with modifiable risk factors for colorectal neoplasms.