This book constitutes the refereed proceedings of the 22nd IFIP WG 5.5 Working Conference on Virtual Enterprises, PRO-VE 2021, held in Saint-Étienne, and virtually in November 2021. The 70 papers (15 full and 55 short) presented with 5 industrial workshop papers were carefully reviewed and selected from 189 submissions. They provide a comprehensive overview of major challenges and recent advances in various domains related to the digital transformation and collaborative networks and their applications with a strong focus on the following areas related to the main theme of the conference: sustainable collaborative networks; sustainability via digitalization; analysis and assessment of business ecosystems; human factors in collaboration 4.0; maintenance and life-cycle management; policies and new digital services; safety and collaboration management; simulation and optimization; complex collaborative systems and ontologies; value co-creation in digitally enabled ecosystems; digitalization strategy in collaborative enterprises’ networks; pathways and tools for DIHs; socio-technical perspectives on smart product-service systems; knowledge transfer and accelerated innovation in FoF; interoperability of IoT and CPS for industrial CNs; sentient immersive response network; digital tools and applications for collaborative healthcare; collaborative networks and open innovation in education 4.0; collaborative learning networks with industry and academia; and industrial workshop.