This article presents a new method to calculate the composition differences (epsilon) for targeting the minimum total annualized cost (TAC) of a mass exchange network (MEN), which is based on the combination of composition interval diagram (CID) with mathematical programming. The total cost target consists of the capital cost of the process units and the operating cost for mass separating agents (MSAs). The value of total cost varies considerably with the composition differences, so the values of epsilon should be optimized in order to obtain minimum TAC of a MEN. This article considers epsilon as a set of unequal variables for each equilibrium equation of a rich-lean stream pair, employing them to build the CID and mathematical model, which optimizes the structure and composition differences simultaneously. Two examples are applied to illustrate the proposed method and the results demonstrate that the approach introduced by this article is simpler and more convenient than the methods in previous literatures.