This book constitutes the refereed proceedings of the 21st International Conference on Runtime Verification, RV 2021, held virtually during October 11-14, 2021. The 11 regular papers and 7 short/tool/benchmark papers presented in this book were carefully reviewed and selected from 40 submissions. Also included is one tutorial paper. The RV conference is concerned with all aspects of monitoring and analysis of hardware, software and more general system executions.