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Background/Objectives: Digital mammography (DM) has long been the standard for breast cancer screening, while digital breast tomosynthesis (DBT) offers an advanced 3D imaging modality capable of generating 2D Synthetic Mammography (SM) images. Despite SM's potential to reduce radiation exposure, many clinics favor DM, with DBT and SM, due to its perceived diagnostic reliability. This study investigates whether radiologists can replace DM with SM in breast cancer screening and diagnosis or if both modalities are necessary. Methods: We retrospectively analyzed DM and SM images from 375 women aged 40–65 who underwent DM with DBT at King Khaled University Hospital from 2020–2022. Three radiologists evaluated the images using ACR BI-RADS, assessing diagnostic accuracy via the area under the receiver operating characteristic (ROC) curve (AUC). The agreement in cancer conspicuity, breast density, size, and calcifications were measured using weighted kappa (κ). Results: Among 57 confirmed cancer cases and 290 cancer-free cases, DM demonstrated higher sensitivity (82.5% vs. 78.9%) and diagnostic accuracy (AUC 0.800 vs. 0.783, p < 0.05) compared to SM. However, SM detected more suspicious calcifications in cancer cases (75.6% vs. 51.2%, p < 0.05). Agreement was fair for conspicuity (κ = 0.288) and calcifications (κ = 0.409), moderate for density (κ = 0.591), and poor for size (κ = 0.254). Conclusions: while SM demonstrates enhanced effectiveness in detecting microcalcifications, DM still proves superior in overall diagnostic accuracy and image clarity. Therefore, although SM offers certain advantages, it remains slightly inferior to DM and cannot yet replace DM in breast cancer screening. [ABSTRACT FROM AUTHOR]