Background Digital breast tomosynthesis (DBT) is considered superior to digital mammography (DM) for women with dense breasts. Purpose To identify differences in screening outcomes, including rates of recall, false-positive (FP) findings, biopsy, cancer detection rate, positive predictive value of recalls and biopsies, and histopathologic tumor characteristics by density using DBT combined with two-dimensional synthetic mammography (SM) (hereafter, DBT+SM) versus DM. Materials and Methods This randomized controlled trial comparing DBT+SM and DM was performed in Bergen as part of BreastScreen Norway, 2016-2017. Automated software measured density (Volpara Density Grade [VDG], 1-4). The outcomes were compared for DBT+SM versus DM by VDG in descriptive analyses. A stratified log-binomial regression model was used to estimate relative risk of outcomes in subgroups by screening technique. Results Data included 28 749 women, 14 380 of whom were screened with DBT+SM and 14 369 of whom were screened with DM (both groups: median age, 59 years; interquartile range [IQR], 54-64 years). The recall rate was lower for women screened with DBT+SM versus those screened with DM for VDG 1 (2.1% [81 of 3929] vs 3.3% [106 of 3212]; P = .001) and VDG 2 (3.2% [200 of 6216] vs 4.3% [267 of 6280]; P = .002). For DBT+SM, adjusted relative risk of recall (VDG 2: 1.8; P < .001; VDG 3: 2.4; P < .001; VDG 4: 1.8; P = .02) and screen-detected breast cancer (VDG 2: 2.4; P = .004; VDG 3: 2.8; P = .01; VDG 4: 2.8; P = .05) increased with VDG, whereas no differences were observed for DM (relative risk of recall for VDG 2: 1.3; P = .06; VDG 3: 1.1; P = .41; VDG 4: 1.1; P = .71; and relative risk of screen-detected breast cancer for VDG 2: 1.7; P = .13; VDG 3: 2.1; P = .06; VDG 4: 2.2; P = .15). Conclusion Screening with digital breast tomosynthesis combined with synthetic two-dimensional mammograms (DBT+SM) versus digital mammography (DM) yielded lower recall rates for women with Volpara Density Grade (VDG) 1 and VDG 2. Adjusted relative risk of recall and screen-detected breast cancer increased with denser breasts for DBT+SM but not for DM. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Sechopoulos and Athanasiou in this issue.