Purpose To evaluate the early implementation of synthesized two-dimensional (s2D) mammography in a population screened entirely with s2D and digital breast tomosynthesis (DBT) (referred to as s2D/DBT) and compare recall rates and cancer detection rates to historic outcomes of digital mammography combined with DBT (referred to as digital mammography/DBT) screening. Materials and Methods This was an institutional review board-approved and HIPAA-compliant retrospective interpretation of prospectively acquired data with waiver of informed consent. Compared were recall rates, biopsy rates, cancer detection rates, and radiation dose for 15 571 women screened with digital mammography/DBT from October 1, 2011, to February 28, 2013, and 5366 women screened with s2D/DBT from January 7, 2015, to June 30, 2015. Two-sample z tests of equal proportions were used to determine statistical significance. Results Recall rate for s2D/DBT versus digital mammography/DBT was 7.1% versus 8.8%, respectively (P < .001). Biopsy rate for s2D/DBT versus digital mammography/DBT decreased (1.3% vs 2.0%, respectively; P = .001). There was no significant difference in cancer detection rate for s2D/DBT versus digital mammography/DBT (5.03 of 1000 vs 5.45 of 1000, respectively; P = .72). The average glandular dose was 39% lower in s2D/DBT versus digital mammography/DBT (4.88 mGy vs 7.97 mGy, respectively; P < .001). Conclusion Screening with s2D/DBT in a large urban practice resulted in similar outcomes compared with digital mammography/DBT imaging. Screening with s2D/DBT allowed for the benefits of DBT with a decrease in radiation dose compared with digital mammography/DBT. RSNA, 2016 An earlier incorrect version of this article appeared online. This article was corrected on August 11, 2016.