This book constitutes the refereed proceedings of the 21st International Symposium on Formal Methods, FM 2016, held in Limassol, Cyprus, in November 2016. The 38 full papers and 11 short papers presented together with one abstract of an invited talk and one invited presentation were carefully reviewed and selected from 162 submissions. The broad topics of interest for FM include: interdisciplinary formal methods; formal methods in practice; tools for formal methods; role of formal methods in software and systems engineering; theoretical foundations.