OBJECTIVE. The objective of our study was to compare the performance of primary 3D search using 360 virtual dissection with primary 2D search using a 2.5- versus a 1.25-mm slice thickness. SUBJECTS AND METHODS. Four hundred fifty-two asymptomatic patients underwent CT colonography (CTC) and colonoscopy. Examinations were reconstructed to 1.25- and 2.5- mm slice thicknesses and interpreted using primary 3D search (360 virtual dissection) and primary 2D search. Two of three experienced reviewers were randomly assigned to each case; 1,808 interpretations were performed. RESULTS. There were 64 adenomas >= 6 mm, 26 of which were large adenomas >= 1 cm. For adenomas 6-9 mm in diameter, the area under the receiver operating characteristic curve (AUC) using 2.5-mm data sets was 0.66, 0.62, 0.90 and 0.78, 0.69, 0.67 for reviewers 1, 2, and 3, respectively, using primary 3D versus 2D search (p = not significant [NS]). For neoplasms = 10 mm, the AUC using 2.5- mm data sets was 0.74, 0.85, 0.89 and 0.66, 0.86, 0.92 for reviewers 1, 2, and 3 using primary 3D versus 2D search (p = NS). There was no significant difference using 1.25- mm collimation. Double review using both primary 3D and 2D search yielded sensitivities of 84% (16/19) and 95% (18/19) for large neoplasms (>= 1 cm) using 2.5- and 1.25mm data sets, respectively. Five of five (100%) adenocarcinomas were identified. The sensitivity of colonoscopy for large neoplasms was 77% (20/26) (20% [1/5] for adenocarcinoma). CONCLUSION. No advantage exists for 1.25- or 2.5- mm slice thickness or for primary 3D versus 2D search at CTC. Double review using primary 3D ( virtual dissection) and 2D search reduces interobserver variability and competes with colonoscopy for the detection of large lesions.