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Background Synthesized mammography (SM) refers to two-dimensional (2D) images derived from the digital breast tomosynthesis (DBT) data. It can reduce the radiation dose and scan duration when compared with conventional full-field digital mammography (FFDM) plus tomosynthesis. Purpose To compare the diagnostic performance of 2D FFDM with synthetic mammograms obtained from DBT in a diagnostic population. Materials and Methods A total of 1,468 mammograms with both FFDM and SM + DBT images were obtained and analyzed over 2 years, after obtaining approval from the institute ethics committee. The images were reported and compared as per the 2013 American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) lexicon in terms of breast density, morphological features of mass, calcifications, and presence of asymmetry or architectural distortion followed by the BI-RADS category. The agreement between the two modalities was studied using the Kappa value, and the radiation exposure dose was recorded in both groups. Results FFDM and SM + DBT showed strong agreement for breast density, mass characteristics, and detection of calcifications (kappa > 0.8). Downstaging of breast density and mass density were seen by SM + DBT without any statistically significant difference. The nipple–areola complex visualization was poor in SM (50.34 vs. 76.29% in FFDM), and there were SM-specific artifacts mainly related to the reconstruction algorithm. The radiation dose was higher with SM. Conclusion FFDM has comparable performance to SM + DBT in diagnostic setup. The latter may be particularly helpful in patients with dense breasts. [ABSTRACT FROM AUTHOR]