This book of Advances in Intelligent and Soft Computing contains accepted papers presented at SOCO 2021 conference held in the beautiful and historic city of Bilbao (Spain), in September 2021. Soft computing represents a collection or set of computational techniques in machine learning, computer science, and some engineering disciplines, which investigate, simulate, and analyze very complex issues and phenomena. After a through peer-review process, the 16th SOCO 2021 International Program Committee selected 78 papers which are published in these conference proceedings and represents an acceptance rate of 48%. In this relevant edition, a special emphasis is put on the organization of special sessions. Seven special sessions are organized related to relevant topics as follows: applications of machine learning in computer vision; soft computing applied to autonomous robots and renewable energy systems; optimization, modeling, and control by soft computing techniques (OMCS);  challenges and new approaches toward artificial intelligence deployments in real-world scenarios; time series forecasting in industrial and environmental applications (TSF); soft computing methods in manufacturing and management systems and applied machine learning. The selection of papers was extremely rigorous in order to maintain the high quality of the conference, and we would like to thank the members of the program committees for their hard work in the reviewing process. This is a crucial process to the creation of a high standard conference, and the SOCO conference would not exist without their help.