The purpose of this study was to compare sensitivity, specificity, and postprocessing time of a colon dissection approach to regular 3D-endoluminal workup of computed tomography (CT) colonography for the detection of polypoid lesions. Twenty-one patients who had received conventional colonoscopy after CT colonography were selected; 18 patients had either colon polyps or colon cancer and three had no findings. CT colonography was performed using a 4-channel multi-detector-row (MDR) CT in ten cases and a 16-channel MDR-CT in 11 cases. A blinded reader retrospectively evaluated all colonographies using both viewing methods in a randomized order. Thirty-seven polyps were identified by optical colonoscopy. An overall per-lesion sensitivity of 47.1% for lesions smaller than 5 mm, 56.3% for lesions between 5 mm and 10 mm, and 75.0% for lesion larger than 10 mm was calculated using the colon dissection approach. This compared to an overall per-lesion sensitivity of 35.3% (<5 mm), 81.5% (5–10 mm), and 100.0% (>10 mm) using the endoluminal view. The average time consumption for CT colonography evaluation with the colon dissection software was 10 min versus 38 min using the endoluminal view. A colon dissection approach may provide a significant time advantage for evaluation of CT colonography while obtaining a high sensitivity. It is especially superior in the detection of lesions smaller than 5 mm.