Based on the three-link energy flow structure theory，an optimization strategy for the distillation process under multiple period operation is presented.The highlights of the strategy are as follows：the problem solution is divided into two levels of single column and column system，and transformed exergy price cU and to-be-recovered exergy price cO are used as the coordination variables.Exergoeconomic models for the optimization of the whole distillation process (including single column and heat integration between columns) are established.The strategy and the model are applied successfully to the optimal design for the column system of a gas separation unit in a refinery under 3 period operation.The optimal scheme proposed is 29.4% less in energy consumption and 21.9% lower in the total cost compared to the exist traditional design.