We evaluated a Pareto front-based multi-objective evolutionary algorithm for optimizing our CT colonography (CTC) computer-aided detection (CAD) system. The system identifies colonic polyps based on curvature and volumetric based features, where a set of thresholds for these features was optimized by the evolutionary algorithm. We utilized a two-fold cross-validation (CV) method to test if the optimized thresholds can be generalized to new data sets. We performed the CV method on 133 patients; each patient had a prone and a supine scan. There were 103 colonoscopically confirmed polyps resulting in 188 positive detections in CTC reading from either the prone or the supine scan or both. In the two-fold CV, we randomly divided the 133 patients into two cohorts. Each cohort was used to obtain the Pareto front by a multi-objective genetic algorithm, where a set of optimized thresholds was applied on the test cohort to get test results. This process was repeated twice so that each cohort was used in the training and testing process once. We averaged the two training Pareto fronts as our final training Pareto front and averaged the test results from the two runs in the CV as our final test results. Our experiments demonstrated that the averaged testing results were close to the mean Pareto front determined from the training process. We conclude that the Pareto front-based algorithm appears to be generalizable to new test data.© (2007) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.