This book constitutes the thoroughly refereed post-conference proceedings of the 4th International Symposium on Combinatorial Optimization, ISCO 2016, held in Vietri sul Mare, Italy, in May 2016. The 38 revised full papers presented in this book were carefully reviewed and selected from 98 submissions. They present original research on all aspects of combinatorial optimization, such as algorithms and complexity; mathematical programming; operations research; stochastic optimization; and graphs and combinatorics.