In this paper, taking desulphurizing ratio and economic cost as two objectives, a ten-input two-output prediction model was structured and validated for desulphurization system. Cerebellar model articulation controller (CMAC) neural network and genetic algorithm (GA) were used for model building and optimization of cost respectively. In the model building process, the grey relation entropy analysis and uniform design method were used to screen the input variables and study the model parameters separately. Traditional regression analysis and proposed location number analysis method were adopted to analyze output errors of experiment group and predict the results of test group. Results show that regression analyses keep high fit degree with experiment group results while the fitting accuracies for test group are quite different. As for location number analysis, a power function between output errors and location numbers was fitted well with the data of experiment group and test group for SO2. Prediction model was initialized by location number analysis method. Model was validated and cost optimization case was performed with GA subsequently. The result shows that the optimal cost obtained from GA could be reduced by more than 30% compared with original optimal operating parameters under same constraints.