This book constitutes the proceedings of the 40th International Conference on Computer Safety, Reliability and Security, SAFECOMP 2021, which took place in York, UK, in September 2021. The 17 full papers included in this volume were carefully reviewed and selected from 76 submissions. They were organized in topical sections as follows: machine learning safety assurance; security engineering; safety and assurance cases; machine learning applications; safety validation and simulation; and fault tolerance.