Objective: This follow-up study of BreastScreen Victoria’s pilot trial of digital breast tomosynthesis aimed to report interval cancer rates, screening sensitivity, and density-stratified outcomes for tomosynthesis vs mammography screening. Methods: Prospective pilot trial [ACTRN-12617000947303] in Maroondah BreastScreen recruited females ≥ 40 years presenting for screening (August 2017–November 2018) to DBT; concurrent screening participants who received mammography formed a comparison group. Follow-up of 24 months from screen date was used to ascertain interval cancers; automated breast density was measured. Results: There were 48 screen-detected and 9 interval cancers amongst 4908 tomosynthesis screens, and 34 screen-detected and 16 interval cancers amongst 5153 mammography screens. Interval cancer rate was 1.8/1000 (95%CI 0.8–3.5) for tomosynthesis vs 3.1/1000 (95%CI 1.8–5.0) for mammography (p = 0.20). Sensitivity of tomosynthesis (86.0%; 95% CI 74.2–93.7) was significantly higher than mammography (68.0%; 95% CI 53.3–80.5), p = 0.03. Cancer detection rate (CDR) of 9.8/1000 (95%CI 7.2–12.9) for tomosynthesis was higher than that of 6.6/1000 (95%CI 4.6–9.2) for mammography (p = 0.08); density-stratified analyses showed CDR was significantly higher for tomosynthesis than mammography (10.6/1000 vs 3.5/1000, p = 0.03) in high-density screens. Recall rate for tomosynthesis was significantly higher than for mammography (4.2% vs 3.0%, p < 0.001), and this increase in recall for tomosynthesis was evident only in high-density screens (5.6% vs 2.9%, p < 0.001). Conclusion: Although interval cancer rates did not significantly differ between screened groups, sensitivity was significantly higher for tomosynthesis than mammography screening. Advances in knowledge: In a program-embedded pilot trial, both increased cancer detection and recall rates from tomosynthesis were predominantly observed in high-density screens.