Screening mammography improves breast cancer outcomes by enabling early detection and treatment. However, false positive callbacks for additional imaging from screening exams cause unnecessary procedures, patient anxiety, and financial burden. This work demonstrates an AI algorithm that reduces false positives by identifying mammograms not suspicious for breast cancer. We trained the algorithm to determine the absence of cancer using 123,248 2D digital mammograms (6,161 cancers) and performed a retrospective study on 14,831 screening exams (1,026 cancers) from 15 US and 3 UK sites. Retrospective evaluation of the algorithm on the largest of the US sites (11,592 mammograms, 101 cancers) a) left the cancer detection rate unaffected (p=0.02, non-inferiority margin 0.25 cancers per 1000 exams), b) reduced callbacks for diagnostic exams by 31.1% compared to standard clinical readings, c) reduced benign needle biopsies by 7.4%, and d) reduced screening exams requiring radiologist interpretation by 41.6% in the simulated clinical workflow. This work lays the foundation for semi-autonomous breast cancer screening systems that could benefit patients and healthcare systems by reducing false positives, unnecessary procedures, patient anxiety, and expenses.