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RATIONALE AND OBJECTIVES With the growing adoption of digital breast tomosynthesis (DBT) in breast cancer screening, we compare the performance of deep learning computer-aided diagnosis on DBT images to that of conventional full-field digital mammography (FFDM). MATERIALS AND METHODS In this study, we retrospectively collected FFDM and DBT images of 78 biopsy-proven lesions from 76 patients. A region of interest was selected for each lesion on FFDM, synthesized 2D, and DBT key slice images. Features were extracted from each lesion using a pretrained convolutional neural network (CNN) and served as input to a support vector machine classifier trained in the task of predicting likelihood of malignancy. RESULTS From receiver operating characteristic (ROC) analysis of all 78 lesions, the synthesized 2D image performed best in both the cradiocaudal view (area under the ROC curve [AUC] = 0.81, SE = 0.05) and mediolateral oblique view (AUC = 0.88, SE = 0.04) in the task of lesion characterization. When cradiocaudal and mediolateral oblique data of each lesion were merged through soft voting, DBT key slice image performed best (AUC = 0.89, SE = 0.04). When only masses and architectural distortions (ARDs) were considered, DBT performed significantly better than FFDM (p = 0.024). CONCLUSION DBT performed significantly better than FFDM in the merged view classification of mass and ARD lesions. The increased performance suggests that the information extracted by the CNN from DBT images may be more relevant to lesion malignancy status than the information extracted from FFDM images. Therefore, this study provides supporting evidence for the efficacy of computer-aided diagnosis on DBT in the evaluation of mass and ARD lesions.