Background: Obesity is associated with an increased risk of colorectal cancer. Derangements in gut hormones that regulate energy balance and metabolism may influence epithelial growth. The aim was to evaluate insulinotropic and digestive hormones in an average risk colorectal cancer (CRC) screening population. Methods: Consecutive patients referred for CRC screening at a municipal hospital were enrolled, and a detailed medical evaluation including height and weight was obtained prior to colonoscopy. A total of 15cc of blood was collected and plasma concentrations of total amylin, acylated ghrelin, glucose-dependent insulinotropic peptide (GIP), active glucagon-like peptide-1 (GLP-1), insulin, leptin, pancreatic polypeptide (PP), and peptide YY (PYY) were measured using a multiplex immunoassay. Based on histologic confirmation of colonoscopic findings, cases (CAs) were defined as individuals with any adenomas regardless of size, including those with villous histology, high-grade dysplasia, or adenocarcinoma. Controls (COs) were selected from individuals without any colonic lesions and matched to the cases based on age, gender, ethnicity, and body mass index. Results: A total of 108 CAs, 56 men and 52 women, (mean age 61 ± 7 years, BMI 26.7 ± 4) were enrolled and matched to 108 COs. The study cohort was composed of Hispanics (58%), Asians (25%), African Americans (14%), and Caucasians (3%). Reflecting fat stores, plasma leptin was significantly correlated to BMI in CAs (r=0.92, p<0.001) and COs (r=0.77, p<0.001). Plasma level of active GLP-1 was markedly elevated in CAs (1130 pg/ml, IQR 548-1610) compared to COs (315 pg/ml, IQR 171-789); p<0.001. Similarly total amylin was significantly elevated in CAs (median 496 pg/ml, IQR 135-754) compared to COs (median 214 pg/ml, IQR 75-471); p<0.001. Although the prevalence of diabetes did not differ between the two groups (25% vs 21%), plasma insulin was lower in CAs (380 pg/ml, IQR 180-566) compared to COs (455 pg/ml, IQR 331-621); p<0.001. Additionally, among women active ghrelin was significantly elevated in CAs (31 pg/ml, IQR 19-49) compared to COs (16 pg/ml, IQR 8-39); p=0.005. Among men, leptin was also significantly elevated in CAs (4235 pg/ml, IQR 1992-6617) compared to COs (2710 pg/ml, IQR 12255245); p=0.047. Conclusions: In this ethnically diverse average risk CRC screening population insulinotropic peptides differentiated individuals with and without colon pathology independent of diabetes. The association of leptin and ghrelin with colon adenomas differs according to gender. Further studies are warranted on the role of gut hormones involved in energy homeostasis and colon cancer development.