This paper presents an optimization-based approach for the multifloor process plant layout problem. The multifloor process plant layout problem involves determining the most efficient-based on predefined criteria-spatial arrangement of a set of process plant equipment with associated connectivity. A number of cost and management/engineering drivers (e.g., connectivity, operations, land area, safety, construction, retrofit, maintenance, production organization) have been considered over the last two decades in order to achieve potential savings in the overall plant design process. This work constitutes an extension of the work by Patsiatzis and Papageorgiou [Ind. Eng. Chem. Res. 2003, 42, 811-824;] to address the multifloor process plant layout problem. New features introduced modeled tall equipment with height greater than the typical floor height in chemical process plants, with connection points at a design-specified height for each piece of equipment. The number of floors, land area, allocation of each piece of equipment to a floor and the overall layout of each floor were determined by the optimization model while preventing overlap of equipment. The connection costs, horizontal and vertical, as well the construction costs were accounted for with an overall objective to minimize the total cost. The problem was formulated as a mixed-integer linear programming (MILP) model based on a continuous domain representation and its applicability demonstrated by a number of illustrative examples. Results showed an increase in the amount of equipment handled by the proposed models in modest computational times. Finally, symmetry breaking constraints were included to increase computational efficiency, and their performance was tested with the last example.