Background: Knowledge of risk factors for interval colorectal neoplasia could inform screening strategies in asymptomatic individuals. Few studies have evaluated risk factors for advanced neoplasia at 5 years in individuals who have had screening colonoscopy. Methods: We studied 1193 participants aged 50-75 to identify factors associated with interval advanced neoplasia during a 5-year follow-up period. Participants underwent screening and 5-year colonoscopy from 1994-1997 at 13 Veterans Affairs Medical Centers. Advanced neoplasia included an adenoma ≥ 1cm, villous histology, high-grade dysplasia, or carcinoma. Risk factors were self-reported at baseline. We performed a multivariable logistic regression analysis of risk for interval advanced neoplasia, adjusting for age, smoking, alcohol use, BMI, colon cancer in first degree relatives, diabetes, cardiovascular disease, and prior outcome. Results: Participants were mostly male (97%) and white (83%). At 5 years, 392 participants (33%) had small adenomas < 1cm, and 92 participants (7.7%) had advanced neoplasia. In multivariable analyses, risk for interval advanced neoplasia was associated with age in 10-year increments (OR, 2.09; 95% CI, 1.39-3.13), diabetes (OR, 1.95; 95% CI, 1.12-3.41), prior small adenomas (OR, 4.02; 95% CI, 1.65-9.80), and prior advanced neoplasia (OR, 12.41; 95% CI, 5.08-30.30). Conclusions: In this prospective screening study, we identified diabetes as an independent risk factor for interval advanced neoplasia. Future guidelines should consider enhanced follow up of diabetic patients.