Abstract: The research about started from the plan of four cascade towers desgin was carried. Firstly, the method of experiment design was using uniform design. Then the incidence formula with the method of binomial stepwise regression was gotten. Last, the optimal operation conditions were gotten by using the method of genetic algorithm. Considering comprehensive factors of drawn from feed rate and from flow rates between cascade column, conclusions were reached on the study of the impact on the abundance of the isotope ¹⁸O. Finally, the incidence formula between the abundance of the isotope ¹⁸O and four operating variables were gotten. Also the incidence formula between heat consumption of the isotope ¹⁸O and four operating variables were gotten. Besides, single factor response diagram of four factors were shown at last. The results showed that the method of simulation and optimization could be applied to ¹⁸O industrial design and would be popular in traditional distillation process to realize optimization design.