Waste Heat Recovery (WHR) by means of an Organic Rankine Cycle is a technology often proposed to reduce the fuel consumption and CO2 emissions of heavy-duty vehicles. A Class 5 Heavy Lorry (tractor) with a WHR system was measured over various driving cycles on the chassis dyno and under realistic conditions on the road, performing each test-cycle with WHR enabled and disabled. The use of WHR lead to reductions in fuel consumption of 3.1% over the World Harmonized Vehicle Cycle, 2.5% over the Regional Delivery Cycle (RDC) and 1.9% over the on-road trips. The WHR system was able to produce more power output during the RDC on the chassis dyno compared to the on-road trips, as more exhaust energy was available during the RDC, resulting in a more considerable reduction of the fuel consumption. No statistically significant reduction of the pollutant emissions was observed. On-road trips were simulated with the Vehicle Energy Consumption calculation Tool, (VECTO), and the fuel consumption was predicted with an error of less than 1.5% for the individual trips and less than 0.5% when averaged over the different repetitions. These findings demonstrate the capability of VECTO to accurately simulate vehicles with Waste Heat Recovery under realistic conditions on the road.