As a promising concept to improve fuel efficiency of a long-haul heavy duty truck with diesel engine, organic Rankine cycle (ORC) based waste heat recovery system (WHR) by utilizing the exhaust gas from internal combustion engine has continuously drawn attention from industry in recent years. The greatest achievable global efficiency may be, however, restricted by the engine. On one hand, engine operating conditions have direct impact on the temperature and the mass flow of exhaust gas, which is the waste heat source, on the other hand, the engine cooling system limits the heat rejection from the condenser of the WHR system. This paper aims to evaluate the impacts of the varied engine applications considering the effects of the WHR system on the global efficiency and engine emissions. A complex 0D/1D-simulation model for a turbocharged production heavy duty engine with low-/high-temperature cooling circuit and a WHR system with ethanol as working fluid have been established in GT-Suite. The WHR-System recovers the heat from high pressure exhaust gas recirculation as well as exhaust gas after turbocharger. The parametric studies have revealed the engine-related restrictions for the global efficiency at WHR-System design operating point. A comparison between one- und two-stage turbochargers in respect of the recovered exergy and an investigation of different integration positions for the WHR-system with respect to the heat rejection potential have been carried out. This paper differs from the most current researches on ORC based WHR-System by the fact that it focuses on the engine performance changes regarding the integration of WHR system rather than the control and optimization of WHR system for a fixed engine configuration.