Colorectal cancer is the third most common incident cancer in the United States and the second cause of cancer deaths in men and women combined. Impairment of DNA mismatch repair (MMR) mechanisms in colonocytes is responsible for about 15% of colorectal cancers. MLH1 and MSH2 proteins play a crucial role in DNA MMR and loss of expression of either (or both) of these proteins is the main cause of DNA MMR insufficiency. These pilot data suggest that lower MLH1 and MSH2 expression in the normal colonic mucosa, at least in the ascending colon, may be associated with increased risk of incident, sporadic colorectal adenoma as well as with modifiable risk factors for colorectal neoplasms, specifically, regular use of NSAIDs. Higher calcium and vitamin D intakes result in increased DNA MMR system activity in the normal colorectal mucosa of sporadic adenoma patients, and the strongest effects may be vitamin D related. These data support further investigation of MLH1 and MSH2 expression as potential modifiable biomarkers of risk for colorectal neoplasms. This work would be interesting for molecular epidemiologists and cancer researchers.