Many medical centers offer digital breast tomosynthesis (DBT) and 2D digital mammography acquired under the same compression (i.e., “Combo” examination) for screening. This paper compares a conventional 2D CAD algorithm (Hologic® ImageChecker® CAD v9.4) for calcification detection against a prototype 3D algorithm (Hologic® ImageChecker® 3D Calc CAD v1.0). Due to the newness of DBT, the development of this 3D CAD algorithm is ongoing, and it is currently not FDA-approved in the United States. For this study, DBT screening cases with suspicious calcifications were identified retrospectively at the University of Pennsylvania. An expert radiologist (E.F.C.) reviewed images with both 2D and DBT CAD marks, and compared the marks to biopsy results. Control cases with one-year negative follow-up were also studied; these cases either possess clearly benign calcifications or lacked calcifications. To allow the user to alter the sensitivity for cancer detection, an operating point is assigned to each CAD mark. As expected from conventional 2D CAD, increasing the operating point in 3D CAD increases sensitivity and reduces specificity. Additionally, we showed that some cancers are occult to 2D CAD at all operating points. By contrast, 3D CAD allows for detection of some cancers that are missed on 2D CAD. We also demonstrated that some non-cancerous CAD marks in 3D are not present at analogous locations in the 2D image. Hence, there are additional marks when using both 2D and 3D CAD in combination, leading to lower specificity than with conventional 2D CAD alone.