To evaluate stand-alone performance of computer-aided detection (CAD) for colorectal polyps of 6 mm or larger at computed tomographic (CT) colonography in a large asymptomatic screening cohort. In this retrospective, institutional review board-approved, HIPAA-compliant study, a CAD software system was applied to screening CT colonography in 1638 women and 1408 men (mean age, 56.9 years) evaluated at a single medical center between March 2006 and December 2008. All participants underwent cathartic preparation with stool tagging; electronic cleansing was not used. The reference standard consisted of interpretation by experienced radiologists in all cases. This interpretation was further refined for the subset of cases with positive findings by using subsequent colonoscopic or CT colonographic confirmation, as well as retrospective expert localization of polyps with CT colonography. This test set was not involved in training the CAD system. The Fisher exact test was used to evaluate significance; 95% confidence intervals (CIs) were obtained by using the exact method. Per-patient CAD sensitivities were 93.8% (350 of 373; 95% CI: 90.9%, 96.1%) and 96.5% (137 of 142; 95% CI: 92.0%, 98.8%) at 6- and 10-mm threshold sizes, respectively. Per-polyp CAD sensitivities for all polyps, regardless of histologic features, were 90.1% (547 of 607; 95% CI: 88.0%, 92.8%) and 96.0% (168 of 175; 95% CI: 91.9%, 98.4%) at 6- and 10-mm threshold sizes, respectively; CAD sensitivities for advanced neoplasia and cancer were 97.0% (128 of 132; 95% CI: 92.4%, 99.2%) and 100% (13 of 13; 95% CI: 79.4%, 100%), respectively. The mean and median false-positive rates were 4.7 and 3 per series, respectively (9.4 and 6 per patient). Among 373 patients with a positive finding at CT colonography, CAD marked an additional 15 polyps of 6 mm or larger, including four large polyps, that were missed at the prospective three-dimensional reading by an expert but were found at subsequent colonoscopy. Stand-alone CAD demonstrated excellent performance for polyp detection in a large screening population, with high sensitivity and an acceptable number of false-positive results.