Clock genes are expressed in a self-perpetuating, circadian pattern in virtually every tissue including the human gastrointestinal tract. They coordinate cellular processes critical for tumor development, including cell proliferation, DNA damage response and apoptosis. Circadian rhythm disturbances have been associated with an increased risk for colon cancer and other cancers. This mechanism has not been elucidated, yet may involve dysregulation of the 'period' (PER) clock genes, which have tumor suppressor properties. A variable number tandem repeat (VNTR) in the PERIOD3 (PER3) gene has been associated with sleep disorders, differences in diurnal hormone secretion, and increased premenopausal breast cancer risk. Susceptibility related to PER3 has not been examined in conjunction with adenomatous polyps. This exploratory case-control study was the first to test the hypothesis that the 5-repeat PER3 VNTR sequence is associated with increased odds of adenoma formation. Information on demographics, medical history, occupation and lifestyle was collected prior to colonoscopy. Cases (n=49) were individuals with at least one histopathologically confirmed adenoma. Controls (n=97) included patients with normal findings or hyperplastic polyps not requiring enhanced surveillance. Unconditional multiple logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs), after adjusting for potential confounding. Adenomas were detected in 34% of participants. Cases were more likely to possess the 5-repeat PER3 genotype relative to controls (4/5 OR, 2.1; 95% CI, 0.9-4.8; 5/5 OR, 5.1; 95% CI, 1.4-18.1; 4/5+5/5 OR, 2.5; 95% CI, 1.7-5.4). Examination of the Oncomine microarray database indicated lower PERIOD gene expression in adenomas relative to adjacent normal tissue. Results suggest a need for follow-up in a larger sample.