Context: Computed tomographic (CT) colonography has been recognized as an alternativefor colorectal cancer (CRC) screening in average-risk individuals, but less information is available on its performance in individuals at increased risk of CRC. Objective: To assess the accuracy of CT colonography in detecting advanced colorectal neoplasia in asymptomatic individuals at increased risk of CRC using unblinded colonoscopy as the reference standard. Design, Setting, and Participants: This was a multicenter, cross-sectional study. Individuals at increased risk of CRC due to either family history of advanced neoplasia in first-degree relatives, personal history of colorectal adenomas, or positive results from fecal occult blood tests (FOBTs) were recruited in 11 Italian centers and 1 Belgian center between December 2004 and May 2007. Each participant underwent CT colonography followed by colonoscopy on the same day. Main Outcome Measures: Sensitivity and specificity of CT colonography in detecting individuals with advanced neoplasia (ie, advanced adenoma or CRC) 6 mm or larger. Results: Of 1103 participants, 937 were included in the final analysis: 373 cases in the family-history group, 343 in the group with personal history of adenomas, and 221 in the FOBT-positive group. Overall, CT colonography identified 151 of 177 participants with advanced neoplasia 6 mm or larger (sensitivity, 85.3%; 95% confidence interval [CI], 79.0%-90.0%) and correctly classified results as negative for 667 of 760 participants without such lesions (specificity, 87.8%; 95% CI, 85.2%-90.0%). The positive and negative predictive values were 61.9% (95% CI, 55.4%-68.0%) and 96.3% (95% CI, 94.6%-97.5%), respectively; after group stratification, a significantly lower negative predictive value was found for the FOBT-positive group (84.9%; 95% CI, 76.2%-91.3%; P_.001). Conclusions In a group of persons at increased risk for CRC, CT colonography compared with colonoscopy resulted in a negative predictive value of 96.3% overall. When limited to FOBT-positive persons, the negative predictive value was 84.9%.