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This study objectively evaluates the similarity between standard full-field digital mammograms and two-dimensional synthesized digital mammograms (2DSM) in a cohort of women undergoing mammography. Under an institutional review board-approved data collection protocol, we retrospectively analyzed 407 women with digital breast tomosynthesis (DBT) and full-field digital mammography (FFDM) examinations performed from September 1, 2014, through February 29, 2016. Both FFDM and 2DSM images were used for the analysis, and 3216 available craniocaudal (CC) and medio