Purpose: To retrospectively evaluate the effect of increasing numbers of computer-aided detection (CAD)-generated false-positive (FP) marks on reader specificity and reporting times by using computed tomographic (CT) colonography in a low-prevalence screening population. Materials and Methods: Ethics committee approval and informed consent were obtained for this HIPAA-compliant study. Four readers each read 48 data sets (26 men, 22 women; mean age, 57 years) from a screening population (three containing polyps) without CAD application, followed by review of the CAD output and recorded findings and diagnostic confidence. The 45 data sets that were designated as normal were chosen such that 22 generated 15 or fewer FP CAD marks and 23 generated more than 15 FP CAD marks. Sensitivity, specificity, and receiver operating characteristic (ROC) curves were calculated with and without CAD. The relationships between the number of CAD FP marks and reader confidence, reporting times, and correct data set classification were analyzed by using linear and logistic regression. Results: Across all readers, CAD resulted in four additional FP detections. Overall reader sensitivity and specificity (6-mm polyp threshold) before and after CAD application were 0.75 (95% confidence interval [CI]: 0.43, 0.95) versus 0.83 (95% CI: 0.52, 0.98) and 0.96 (95% CI: 0.91, 0.98) versus 0.93 (95% CI: 0.88, 0.96), respectively. The area under the ROC curve increased from 0.57 (95% CI: 0.34, 0.80) to 0.61 (95% CI: 0.42, 0.80). There was no correlation between an increasing number of CAD FP marks and reader confidence (P = .71) or correct study classification (P = .23), but there was a positive correlation with CAD-assisted reading times (0.06 [95% CI: 0.02, 0.10], P = .002). Conclusion: Increasing numbers of CAD FP marks did not adversely influence correct reader study classification or diagnostic confidence, although reporting times did increase. (c) RSNA, 2008.