Malfunctioning of the adenomatous polyposis coli (APC)/β-catenin signaling pathway is both an early and common event in sporadic colorectal cancer. To assess the potential of APC/β-catenin signaling pathway markers as treatable, preneoplastic biomarkers of risk for colorectal neoplasms, we conducted a pilot colonoscopy-based case-control study (51 cases and 154 controls) of incident, sporadic colorectal adenoma. We evaluated APC, β-catenin, and E-cadherin expression in normal mucosa from the rectum and ascending and sigmoid colon using automated immunohistochemical and quantitative image analysis. Diet, lifestyle, and medical history were assessed with validated questionnaires. In the normal rectal mucosa, the ratio of the proportion of APC expression in the upper 40% of crypts with total β-catenin expression (APC/β-catenin score) was 14.3% greater in controls than in cases [P = 0.02; OR, 0.40; 95% confidence interval (CI), 0.14-1.14]. Compared with controls, in cases, APC expression was 3.2% lower, β-catenin expression was 3.0% higher, and E-cadherin expression was 0.7% lower; however, none of these differences were statistically significant. The APC/β-catenin score statistically significantly differed according to categories of plausible risk factors for colorectal cancer [e.g., it was 17.7% higher among those with 25(OH) vitamin D(3) concentrations ≥ 27 ng/mL]. These preliminary data suggest that the combined expression of APC and β-catenin in the normal rectal mucosa may be associated with risk for incident, sporadic colorectal neoplasms, as well as with modifiable risk factors for colorectal neoplasms. Our results may help advance the development of treatable, preneoplastic biomarkers of risk for colorectal neoplasms.