This paper addresses the application of Genetic Programming (GP) to the synthesis of heat-integrated complex distillation system and the flowsheet of complex separation can be expressed directly using GP's special hierarchical structure. A series of unique encoding method and solution strategy is proposed and some evolutionary factor is improved based on the domain knowledge of chemical engineering. A shortcut method is applied to calculate all required design parameters. Conventional and complex columns, thermally coupled (linked) side strippers and side rectifiers, fully thermally coupled columns as well as heat integration between any different columns are simultaneously considered. Two illustrating examples are presented to demonstrate the effective computational strategies. (C) 2007 Elsevier Ltd. All rights reserved.