This paper presents a general mathematical programming formulation for the multi-floor process plant layout problem, which considers a number of cost and management/engineering drivers within the same framework thus resolving various trade-offs at an optimal manner. The proposed model determines simultaneously the number of floors, land area, floor allocation of each equipment item and detailed layout for each floor. The overall problem is formulated as a mixed integer linear programming (MILP) model based on a continuous domain representation. The applicability of the model is demonstrated by three illustrative examples.