Safety is the focus of attention in plant layout problems. Previous studies have often expressed safety as a cost of risk, that is, the cost of property losses that may occur in an accident. In this paper, the influence of uncertainty on the equipment vulnerability is quantitatively considered and a more reliable process plant layout is proposed. The equipment vulnerability index is used to evaluate the vulnerability level of the target equipment in case of an accident, which is applied to propose a mixed-integer nonlinear optimized process plant layout to minimize domino risk. In addition, a decision matrix is applied to determine whether the risk level of the optimized layout of the target equipment is acceptable. Damage probability and vulnerability are the basic inputs of this matrix. The proposed method was applied to a coal-water slurry gasification process and the results show that the layout obtained by the proposed model has better practical value than the current layout, reducing the domino risk by 53.2%. Meanwhile, the model can be used to identify critical equipment and select targeted safety measures during the production stage.