A complex simulation model of a heavy duty truck, including an Organic Rankine Cycle (ORC) based waste heat recovery system and a vehicle cooling system, was applied to determine the system fuel economy potential in a typical drive cycle. Measures to increase the system performance were investigated and a comparison between two different cooling system designs was derived. The base design, which was realized on a Mercedes-Benz Actros vehicle revealed a fuel efficiency benefit of 2.6%, while a more complicated design would generate 3.1%. Furthermore, fully transient simulation results were performed and are compared to steady state simulation results. It is shown that steady state simulation can produce comparable results if averaged road data are used as boundary conditions.