A general mathematical programming formulation which also considers safety factors is presented for solving the multi-floor plant layout problem. In the presence of a risk of physical explosion, the safety distance must be considered to generate more reasonable and safe layouts. The proposed method determines detailed multi-floor process plant layouts using mixed integer linear programming (MILP). To consider the safety distance, a consequence analysis is adopted for calculating an equipment physical explosion probit. As the TNT equivalency method is used, more realistic estimations of equipment damage are possible, generating safer plant layouts. The objective function minimizes the layout cost (total plant area, floor construction costs and connection costs) and explosion damage costs for the multi-floor problem. Two illustrative examples are presented to demonstrate the applicability of the proposed method.