This book constitutes the refereed post-conference proceedings of 9 workshops held at the 35th International ISC High Performance 2021 Conference, in Frankfurt, Germany, in June-July 2021: Second International Workshop on the Application of Machine Learning Techniques to Computational Fluid Dynamics and Solid Mechanics Simulations and Analysis; HPC-IODC: HPC I/O in the Data Center Workshop; Compiler-assisted Correctness Checking and Performance Optimization for HPC; Machine Learning on HPC Systems;4th International Workshop on Interoperability of Supercomputing and Cloud Technologies;2nd International Workshop on Monitoring and Operational Data Analytics;16th Workshop on Virtualization in High­-Performance Cloud Computing; Deep Learning on Supercomputers; 5th International Workshop on In Situ Visualization. The 35 papers included in this volume were carefully reviewed and selected. They cover all aspects of research, development, and application of large-scale,high performance experimental and commercial systems. Topics include high-performance computing (HPC), computer architecture and hardware, programming models, system software, performance analysis and modeling, compiler analysis and optimization techniques, software sustainability, scientific applications, deep learning. Chapter “Machine-Learning-Based Control of Perturbed and Heated Channel Flows” is available open access under a Creative Commons Attribution 4.0 International License via link.springer.com.