Rationale and Objectives: Information evaluating the efficacy of 2D synthesized mammography (2Ds) reconstructions in microcalcification detection is limited. This study used stereotactic biopsy data for microcalcifications to evaluate the stepwise implementation of 2Ds in screening mammography. The study aim was to identify whether 2Ds + digital breast tomosynthesis (DBT) is non-inferior to 2D digital mammography (2DM) + 2Ds + DBT, 2DM + DBT, and 2DM in identifying microcalcifications undergoing further diagnostic imaging and stereotactic biopsy. Materials and Methods: Retrospective stereotactic biopsy data were extracted following 151,736 screening mammograms of healthy women (average age, 56.3 years; range, 30–89 years), performed between 2012 and 2019. The stereotactic biopsy data were separated into 2DM, 2DM + DBT, 2DM + 2Ds + DBT, and 2Ds + DBT arms and examined using Fisher’s exact test to compare the detection rates of all cancers, invasive cancers, DCIS, and ADH between modalities for patients undergoing stereotactic biopsy of microcalcifications. Results: No statistical significance in cancer detection was seen for 2Ds + DBT among those calcifications that underwent stereotactic biopsy when comparing the 2Ds + DBT to 2DM, 2DM + DBT, and 2DM + 2Ds + DBT imaging combinations. Conclusion: These data suggest that 2Ds + DBT is non-inferior to 2DM + DBT in detecting microcalcifications that will undergo stereotactic biopsy.