This book constitutes the refereed proceedings of the 21st IFIP WG 6.1 International Conference on Distributed Applications and Interoperable Systems, DAIS 2021, held in Valletta, Malta, in June 2021, as part of the 16th International Federated Conference on Distributed Computing Techniques, DisCoTec 2021. The 7 regular papers and 3 short papers presented in this book were carefully reviewed and selected from 15 submissions. DAIS addresses all practical and conceptual aspects of distributed applications, including their design, modeling, implementation and operation, the supporting middleware, appropriate software engineering methodologies and tools, as well as experimental studies and applications.