Oxime exchange is a novel process preparing acetaldehyde oxime, but some disadvantages in the reaction process also exist, such as easily oxidized acetaldoxime by air, many azeotropes in the reaction solution, and hardly separated and purified acetaldoxime.The oxidation of acetaldehyde oxime and volatilization of acetaldehyde and butanone oxime were avoided using 0.2 MPa nitrogen as protective gas during the reaction process. The selectivity of acetaldehyde oxime is 96.12%. Moreover, an effective purification process of the product was developed. Firstly, the basic process of separation of reaction liquid by vacuum distillation was simulated by Aspen plus. The influences of pressure, plate number, reflux ratio and feed position on the separation process were investigated. According to the operating parameters of simulation, the optimum separation and purification process in actual reaction were determined. In this condition, the purity of the resulting acetaldoxime is 95.33% with the yield of 94.31%. This work could provide guidance for the industrialization of acetaldehyde oxime by oxime exchange method.