The incidence of colorectal cancer in patients undergoing colonoscopic surveillance is higher than previously thought. A better understanding of interval cancers is needed to improve surveillance strategies. The objectives of this study were to determine whether interval colorectal cancers were associated with an inadequate earlier colonoscopy, incomplete polypectomy, or aggressive biologic behavior. We searched our institution's cancer registry. Interval cancers were defined as colorectal cancers that developed within 5 years of a complete colonoscopy. These were frequency matched in a 1:2 ratio to patients with sporadic cancers, which were defined as colorectal cancers diagnosed on a patient's first recorded colonoscopy. Patient, colonoscopy, and tumor characteristics of interval and sporadic cancers were compared. Of the 830 colorectal cancers diagnosed during the study period, 45 patients developed an interval cancer (5.4%; 95% confidence interval, 4.1%-7.2%). Twenty-seven percent of interval cancers developed at previous polypectomy segments, and location of polypectomy segments was predictive of the location of subsequent interval cancers. Interval cancers were 3 times more likely to occur in the right colon and were smaller in size than sporadic cancers. Quality of bowel preparation, individual endoscopist, endoscopist experience, and trainee involvement were not associated with interval cancers. No difference in TNM stage at diagnosis, histologic type or grade, carcinoembryonic antigen level, or 5-year survival was found between interval and sporadic cancers. Incomplete polypectomy might play an important role in the development of interval colorectal cancer. No association between other colonoscopy-related factors or tumor characteristics and interval cancers was found.