This work describes a working fluid selection process for an ORC based power plant that uses as heat source waste heat from a petroleum distillation furnace. Sixteen (16) organic fluids previously considered for similar applications are analyzed based on environmental, safety and physical properties. Two different power plants layouts, a basic one and another featuring an internal heat exchanger (IHE), are analyzed. The combinations between working fluids and plant layouts seek to maximize the ORC-based power plant thermal efficiency. ORC exergy destruction and exergy efficiency are also accounted for. In this work, the close interrelation between working fluids thermo-physical properties and expander dimensionless characteristics is also assessed. The main results indicate that R245ca and R245fa are the working fluid leading to both the highest thermal (∼16%) and exergy efficiencies (∼23%), and the lowest exergy destructions (∼703 kW). Based on required properties of the selected working fluid, an axial turbine design seems to be the most appropriate ORC expander technology for the particular application discussed in this paper. The outcomes from this work will be used as the basis for the detailed design of the components of an ORC-based power plant focused on increasing the overall efficiency of petroleum distillation processes.