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This book constitutes the refereed proceedings of the 21st International Conference on Artificial Intelligence in Medicine, AIME 2023, held in Portoroz, Slovenia, in June12-15, 2023. The 23 full papers and 21 short papers presented together with 3 demonstration papers were selected from 108 submissions. The papers are grouped in topical sections on: machine learning and deep learning; explainability and transfer learning; natural language processing; image analysis and signal analysis; data analysis and statistical models; knowledge representation and decision support.