The separation of aqueous acetonitrile solution by pressure swing distillation (PSD) was simulated and optimized through Aspen Plus software. The distillation sequence of the low pressure column (LPC) and high pressure column (HPC) was determined with a phase diagram. The pressures of the two columns were set to 1 and 4 atm, respectively. Total annual cost (TAC) was considered as the objective function, and design variables, such as the tray number, the reflux ratio, and the feeding position, were optimized. The optimum process parameters were obtained. For the reduction of energy consumption, the PSD with full-heat integration was designed. The TAC of this method is lower by 32.39% of that of the PSD without heat integration. Therefore, it is more economical to separate acetonitrile and water mixture by PSD with full-heat integration, which provides technical support for the separation design of such azeotropes.