Given the limited access to breast cancer (BC) screening, the authors developed and validated a mobile phone-artificial intelligence-based infrared thermography (AI-IRT) system for BC screening.This large prospective clinical trial assessed the diagnostic performance of the AI-IRT system. The authors constructed two datasets and two models, performed internal and external validation, and compared the diagnostic accuracy of the AI models and clinicians. Dataset A included 2100 patients recruited from 19 medical centres in nine regions of China. Dataset B was used for independent external validation and included 102 patients recruited from Langfang People's Hospital.The area under the receiver operating characteristic curve of the binary model for identifying low-risk and intermediate/high-risk patients was 0.9487 (95% CI: 0.9231-0.9744) internally and 0.9120 (95% CI: 0.8460-0.9790) externally. The accuracy of the binary model was higher than that of human readers (0.8627 vs. 0.8088, respectively). In addition, the binary model was better than the multinomial model and used different diagnostic thresholds based on BC risk to achieve specific goals.The accuracy of AI-IRT was high across populations with different demographic characteristics and less reliant on manual interpretations, demonstrating that this model can improve pre-clinical screening and increase screening rates.Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.