In a modern internal combustion engine, most of the fuel energy is dissipated as heat, mainly in the form of hot exhaust gas. A high temperature is required to allow conversion of the engine-out emissions in the catalytic system, but the temperature is usually still high downstream of the exhaust gas aftertreatment system. One way to recover some of this residual heat is to implement a Rankine cycle, which is connected to the exhaust system via a heat exchanger. The relatively low weight increase due to the additional components does not cause a significant fuel penalty, particularly for heavy-duty vehicles.The efficiency of a waste-heat recovery system such as a Rankine cycle depends on the efficiencies of the individual components and the choice of a suitable working fluid for the given boundary conditions. Commonly used pure working fluids have the drawback of an isothermal evaporation and condensation, which increases irreversibility, and consequently decreases the efficiency during the heat transfer. Previous work has suggested that one way to overcome this problem is to use zeotropic mixed working fluids. These have already been applied in several stationary systems and refrigerant cycles but not yet in waste-heat recovery systems for portable applications.This theoretical study compares different pure working fluids and zeotropic mixtures in both subcritical and supercritical Rankine cycles. The main objective was to analyze the respective energy and exergy efficiencies by modeling the Rankine cycles. The results suggested that the final fluid and cycle choice is limited by the exhaust-gas temperature range of a heavy-duty diesel engine and realistic condensation conditions for the fluid. Further, environmental and safety concerns over working fluids in portable applications are important challenges, which need to be taken into account in selecting an appropriate fluid.