BackgroundDouble reading (DR) in screening mammography increases cancer detection and lowers recall rates, but has sustainability challenges due to workforce shortages. Artificial intelligence (AI) as an independent reader (IR) in DR may provide a cost-effective solution with the potential to improve screening performance. Evidence for AI to generalise across different patient populations, screening programmes and equipment vendors, however, is still lacking.MethodsThis retrospective study simulated DR with AI as an IR, using data representative of real-world deployments (275,900 cases, 177,882 participants) from four mammography equipment vendors, seven screening sites, and two countries. Non-inferiority and superiority were assessed for relevant screening metrics.ResultsDR with AI, compared with human DR, showed at least non-inferior recall rate, cancer detection rate, sensitivity, specificity and positive predictive value (PPV) for each mammography vendor and site, and superior recall rate, specificity, and PPV for some. The simulation indicates that using AI would have increased arbitration rate (3.3% to 12.3%), but could have reduced human workload by 30.0% to 44.8%.ConclusionsAI has potential as an IR in the DR workflow across different screening programmes, mammography equipment and geographies, substantially reducing human reader workload while maintaining or improving standard of care.Trial registrationISRCTN18056078 (20/03/2019; retrospectively registered).Supplementary InformationThe online version contains supplementary material available at 10.1186/s12885-023-10890-7.