Purpose To determine whether the rates and tumor characteristics of screening-detected and interval cancers differ for two-dimensional digital mammography (DM) versus digital breast tomosynthesis (DBT) mammography. Materials and Methods Consecutive screening mammograms from January 2009 to February 2011 (DM group, before DBT integration) and from January 2013 to February 2015 (DBT group, after complete DBT integration) were reviewed. Cancers were considered screening detected if diagnosed within 365 days of a positive screening examination and interval if diagnosed within 365 days of a negative screening examination. Z tests were used to compare cancers on DM versus DBT examinations. Results A total of 948 breast cancers were diagnosed after 78 385 DM and 76 896 DBT examinations. Although the overall rate of screening-detected cancers was similar with DM and DBT (5.0 vs 5.0 per 1000 examinations, P = .98), a higher proportion of screening-detected cancers were invasive rather than in situ with DBT (74.2% [287 of 387] vs 66.0% [260 of 394], P = .01). There were no significant differences in tumor characteristics, including size at pathologic examination, grade, hormone receptor status, and nodal status, between the screening-detected invasive cancers on DM versus DBT (P = .09-.99). The rate of interval cancers was similar with DM and DBT (1.1 vs 1.1 per 1000 examinations, P = .84). Compared with symptomatic interval cancers, magnetic resonance imaging-detected interval cancers were more likely to be minimal cancers. Conclusion The overall rates of screening-detected and interval cancers are similar with DM and DBT, but a higher proportion of screening-detected cancers are invasive rather than in situ with DBT. © RSNA, 2017.