Purpose To compare the clinical performance of synthesized two-dimensional (s2D) mammography combined with digital breast tomosynthesis (DBT) with that of full-field digital mammography (FFDM) alone and FFDM combined with DBT in a large community-based screening population by analyzing recall rate, positive predictive value, and cancer detection rate. Materials and Methods This was a retrospective study approved by the institutional review board and was HIPAA compliant with waiver of informed consent. A total of 78 810 screening mammograms from October 11, 2011, to June 30, 2016, were retrospectively collected. Of these, 32 076 were FFDM, 30 561 were DBT-FFDM, and 16 173 were DBT-s2D mammograms. Diagnostic performance of FFDM, DBT-FFDM, and DBT-s2D mammography was compared. Statistical significance was determined by using the Pearson χ2 test and was expressed as odds ratios and related confidence intervals determined by means of logistic regression analysis with pairwise comparisons. Results Recall rates were significantly lower with DBT-s2D mammography (4.3%, 687 of 16 173) when compared with DBT-FFDM (5.8%, 1785 of 30 561; odds ratio, 0.72; 95% confidence interval: 0.65, 0.78; P < .0001) and when compared with FFDM alone (8.7%, 2799 of 32 076; odds ratio, 0.46; 95% confidence interval: 0.43, 0.51). The cancer detection rate was similar among FFDM alone (5.3 of 1000 screening examinations), DBT-FFDM (6.4 of 1000 screening examinations), and DBT-s2D mammography (6.1 of 1000 screening examinations) with no significant difference (FFDM vs DBT-FFDM, P = .08; FFDM vs DBT-s2D, P = .27). The percentage of invasive cancers detected was significantly higher with DBT-s2D mammography (76.5%) than with DBT-FFDM (61.3%, P = .01), and positive predictive values with DBT-s2D mammography (40.8%) were significantly higher than those with DBT-FFDM (28.5%, P < .0001). Conclusion Screening with DBT-s2D mammography in a large community-based practice improved recall rate and positive predictive values without loss of cancer detection rate when compared with DBT-FFDM and FFDM alone. © RSNA, 2017.