This two-volume set LNCS 12861 and LNCS 12862 constitutes the refereed proceedings of the 16th International Work-Conference on Artificial Neural Networks, IWANN 2021, held virtually, in June 2021.The 85 full papers presented in this two-volume set were carefully reviewed and selected from 134 submissions. The papers are organized in topical sections on Deep Learning for Biomedicine, Intelligent Computing Solutions for SARS-CoV-2 Covid-19, Advanced Topics in Computational Intelligence, Biosignals Processing, Neuro-Engineering and much more.