IntroductionArtificial intelligence (AI) algorithms for interpreting mammograms have the potential to improve the effectiveness of population breast cancer screening programmes if they can detect cancers, including interval cancers, without contributing substantially to overdiagnosis. Studies suggesting that AI has comparable or greater accuracy than radiologists commonly employ ‘enriched’ datasets in which cancer prevalence is higher than in population screening. Routine screening outcome metrics (cancer detection and recall rates) cannot be estimated from these datasets, and accuracy estimates may be subject to spectrum bias which limits generalisabilty to real-world screening. We aim to address these limitations by comparing the accuracy of AI and radiologists in a cohort of consecutive of women attending a real-world population breast cancer screening programme.Methods and analysisA retrospective, consecutive cohort of digital mammography screens from 109 000 distinct women was assembled from BreastScreen WA (BSWA), Western Australia’s biennial population screening programme, from November 2016 to December 2017. The cohort includes 761 screen-detected and 235 interval cancers. Descriptive characteristics and results of radiologist double-reading will be extracted from BSWA outcomes data collection. Mammograms will be reinterpreted by a commercial AI algorithm (DeepHealth). AI accuracy will be compared with that of radiologist single-reading based on the difference in the area under the receiver operating characteristic curve. Cancer detection and recall rates for combined AI–radiologist reading will be estimated by pairing the first radiologist read per screen with the AI algorithm, and compared with estimates for radiologist double-reading.Ethics and disseminationThis study has ethical approval from the Women and Newborn Health Service Ethics Committee (EC00350) and the Curtin University Human Research Ethics Committee (HRE2020-0316). Findings will be published in peer-reviewed journals and presented at national and international conferences. Results will also be disseminated to stakeholders in Australian breast cancer screening programmes and policy makers in population screening.