A computer-aided detection system to detect clustered microcalcifications in digital breast tomosynthesis (DBT) is disclosed. The system performs detection in 2D images and a reconstructed 3D volume. The system may include an initial prescreening of potential microcalcifications by using one or more 3D calcification response function (CRF) values modulated by an enhancement method to identify high response locations in the DBT volume as potential signals. Microcalcifications may be enhanced using a Multi-Channel Enhancement method. Locations detected using these methods can be identified and the potential microcalcifications may be extracted. The system may include object segmentation that uses region growing guided by the enhancement-modulated CRF values, gray level voxel values relative to a local background level, or the original DBT voxel values. False positives may be reduced by descriptors of characteristics of microcalcifications. Detected locations of clusters and a cluster significance rating of each cluster may be output and displayed.