Purpose To compare digital mammography (DM) plus digital breast tomosynthesis (DBT) versus DM alone for breast cancer screening in the Reggio Emilia Tomosynthesis trial, a two-arm test-and-treat randomized controlled trial. Materials and Methods For this trial, eligible women (45-70 years old) who previously participated in the Reggio Emilia screening program were invited for mammography. Consenting women were randomly assigned 1:1 to undergo DBT+DM or DM (both of which involved two projections and double reading). Women were treated according to the decision at DBT+DM. Sensitivity, recall rate, and positive predictive value (PPV) at baseline were determined; the ratios of these rates for DBT+DM relative to DM alone were determined. Results From March 2014 to March 2016, 9777 women were recruited to the DM+DBT arm of the study, and 9783 women were recruited to the DM arm (mean age, 56.2 vs 56.3 years). Recall was 3.5% in both arms; detection was 4.5 per 1000 (44 of 9783) and 8.6 per 1000 (83 of 9777), respectively (+89%; 95% confidence interval [CI]: 31, 72). PPV of the recall was 13.0% and 24.1%, respectively (P = .0002); 72 of 80 cancers found in the DBT+DM arm and with complete DBT imaging were positive at least at one DBT-alone reading. The greater detection rate for DM+DBT was stronger for ductal carcinoma in situ (+180%, 95% CI: 1, 665); it was notable for small and medium invasive cancers, but not for large ones (+94 [95% CI: 6, 254]; +122 [95% CI: 18, 316]; -12 [95% CI: -68, 141]; for invasive cancers < 10 mm, 10-19 mm, and ≥ 20 mm, respectively). Conclusion DBT+DM depicts 90% more cancers in a population previously screened with DM, with similar recall rates.