Background Retrospective studies have suggested that using artificial intelligence (AI) may decrease the workload of radiologists while preserving mammography screening performance. Purpose To compare workload and screening performance for two cohorts of women who underwent screening before and after AI system implementation. Materials and Methods This retrospective study included 50-69-year-old women who underwent biennial mammography screening in the Capital Region of Denmark. Before AI system implementation (October 1, 2020, to November 17, 2021), all screenings involved double reading. For screenings conducted after AI system implementation (November 18, 2021, to October 17, 2022), likely normal screenings (AI examination score ≤5 before May 3, 2022, or ≤7 on or after May 3, 2022) were single read by one of 19 senior full-time breast radiologists. The remaining screenings were read by two radiologists with AI-assisted decision support. Biopsy and surgical outcomes were retrieved between October 1, 2020, and April 15, 2023, ensuring at least 180 days of follow-up. Screening metrics were compared using the χ2 test. Reading workload reduction was measured as saved screening reads. Results In total, 60 751 and 58 246 women were screened before and after AI system implementation, respectively (median age, 58 years [IQR, 54-64 years] for both cohorts), with a median screening interval before AI of 845 days (IQR, 820-878 days) and with AI of 993 days (IQR, 968-1013 days; P < .001). After AI system implementation, the recall rate decreased by 20.5% (3.09% before AI [1875 of 60 751] vs 2.46% with AI [1430 of 58 246]; P < .001), the cancer detection rate increased (0.70% [423 of 60 751] vs 0.82% [480 of 58 246]; P = .01), the false-positive rate decreased (2.39% [1452 of 60 751] vs 1.63% [950 of 58 246]; P < .001), the positive predictive value increased (22.6% [423 of 1875] vs 33.6% [480 of 1430]; P < .001), the rate of small cancers (≤1 cm) increased (36.6% [127 of 347] vs 44.9% [164 of 365]; P = .02), the rate of node-negative cancers was unchanged (76.7% [253 of 330] vs 77.8% [273 of 351]; P = .73), and the rate of invasive cancers decreased (84.9% [359 of 423] vs 79.6% [382 of 480]; P = .04). The reading workload was reduced by 33.5% (38 977 of 116 492 reads). Conclusion In a population-based mammography screening program, using AI reduced the overall workload of breast radiologists while improving screening performance. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Lee and Friedewald in this issue.