This book constitutes the refereed proceedings of the 16th International Conference on Critical Information Infrastructures Security, CRITIS 2021, which took place in Lausanne, Switzerland, during September 27-29, 2021.The 12 full papers included in this volume were carefully reviewed and selected from 42 submissions. They were organized in topical sections as follows: protection of cyber-physical systems and industrial control systems (ICS); C(I)IP organization, (strategic) management and legal aspects; human factor, security awareness and crisis management for C(I)IP and critical services; and future, TechWatch and forecast for C(I)IP and critical services.