The objective of our study was to assess the value of two-way interpretation (i.e., from rectum to cecum and vice versa) compared with one-way interpretation (i.e., from rectum to cecum only) in terms of polyp detection and interpretation time on MDCT colonography. Fifty consecutive patients underwent both CT colonography and conventional colonoscopy. Three radiologists independently analyzed the CT colonographic examinations of each patient using a primary 3D method. All examinations were analyzed using two techniques: navigation from rectum to cecum only (one-way) and navigation from rectum to cecum and vice versa (two-way). Sensitivity and positive predictive value were calculated on both a per-polyp basis and a per-patient basis. Alternative free-response receiver operating characteristic (ROC) curve analysis was estimated, and image interpretation time was documented. One hundred fifty-five polyps were depicted in 45 patients by colonoscopy. The mean sensitivity of CT colonography for polyp detection with two-way (88.4%) was significantly superior to that with one-way (78.1%) (p < 0.01). The mean positive predictive value of each observer with one-way was 66.7%, whereas that with two-way was 65.8%. The mean area under the alternative free-response ROC curve (A(z) value) with two-way (0.827) was higher than that with one-way (0.816), but there was not a statistically significant difference. The average interpretation time of each observer with two-way (39 min) was statistically significantly longer than that with one-way (25 min) (p < 0.01). When using a primary 3D interpretation technique at CT colonography, complete 3D navigation from rectum to cecum and from cecum to rectum is mandatory to maximize polyp detection. The image interpretation time for two-way interpretation is statistically significantly longer than that with one-way interpretation.