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.