Objective: To assess performance endpoints of a combination of digital breast tomosynthesis (DBT) and full-field digital mammography (FFDM) compared with FFDM only in breast cancer screening. Materials and methods: This was a prospective population-based screening study, including eligible (50–69 years) women attending the Capital Region Mammography Screening Program in Denmark. All attending women were offered FFDM. A subgroup was consecutively allocated to a screening room with DBT. All FFDM and DBT underwent independent double reading, and all women were followed up for 2 years after screening date or until next screening date, whichever came first. Results: 6353 DBT + FFDM and 395 835 FFDM were included in the analysis and were undertaken in 196 267 women in the period from 1 November 2012 to 12 December 2018. Addition of DBT increased sensitivity: 89.9% (95% confidence interval (CI): 81.0–95.5) for DBT + FFDM and 70.1% (95% CI: 68.6–71.6) for FFDM only, p < 0.001. Specificity remained similar: 98.2% (95% CI: 97.9–98.5) for DBT + FFDM and 98.3% (95% CI: 98.2–98.3) for FFDM only, p = 0.9. Screen-detected cancer rate increased statistically significantly: 11.18/1000 for DBT + FFDM and 6.49/1000 for FFDM only, p < 0.001. False-positive rate was unchanged: 1.75% for DBT + FFDM and 1.73% for FFDM only, p = 0.9. Positive predictive value for recall was 39.0% (95% CI: 31.9–46.5) for DBT + FFDM and 27.3% (95% CI: 26.4–28.2), for FFDM only, p < 0.0005. The interval cancer rate decreased: 1.26/1000 for DBT + FFDM and 2.76/1000 for FFDM only, p = 0.02. Conclusion: DBT + FFDM yielded a statistically significant increase in cancer detection and program sensitivity.