Purpose To examine the outcomes of a breast cancer screening program based on digital breast tomosynthesis (DBT) plus synthesized two-dimensional (2D) mammography compared with those after full-field digital mammography (FFDM). Materials and Methods This prospective study included 16 666 asymptomatic women aged 50-69 years who were recruited in April 2015 through March 2016 for DBT plus synthetic 2D screening in the Verona screening program. A comparison cohort of women screened with FFDM (n = 14 423) in the previous year was included. Screening detection measures for the two groups were compared by calculating the proportions associated with each outcome, and the relative rates (RRs) were estimated with multivariate logistic regression. Results Cancer detection rate (CDR) for DBT plus synthetic 2D imaging was 9.30 per 1000 screening examinations versus 5.41 per 1000 screening examinations with FFDM (RR, 1.72; 95% confidence interval [CI]: 1.30, 2.29). CDR was significantly higher in patients screened with DBT plus synthetic 2D imaging than in those screened with FFDM among women classified as having low breast density (RR, 1.53; 95% CI: 1.13, 2.10) or high breast density (RR, 2.86; 95% CI: 1.42, 6.25). The positive predictive value (PPV) for recall was almost doubled with DBT plus synthetic 2D imaging: 23.3% versus 12.9% of recalled patients who were screened with FFDM (RR, 1.81; 95% CI: 1.34, 2.47). The recall rate was similar between groups (RR, 0.95; 95% CI: 0.84, 1.06), whereas the recall rate with invasive assessment was higher for DBT plus synthetic 2D imaging than for FFDM (RR, 1.93; 95% CI: 1.31, 2.03). The mean number of screening studies interpreted per hour was significantly lower for screening examinations performed with DBT plus synthetic 2D imaging (38.5 screens per hour) than with FFDM (60 screens per hour) (P < .001). Conclusion DBT plus synthetic 2D imaging increases CDRs with recall rates comparable to those of FFDM. DBT plus synthetic 2D imaging increased image reading time and the time needed for invasive assessments. © RSNA, 2017.