Heavy-duty vehicles (HDVs) account for some 5% of the EU’s total greenhouse gas emissions. They present a variety of possible configurations that are deployed depending on the intended use. This variety makes the quantification of their CO2 emissions and fuel consumption difficult. For this reason, the European Commission has adopted a simulation-based approach for the certification of CO2 emissions and fuel consumption of HDVs in Europe; the VECTO simulation software has been developed as the official tool for the purpose. The current study investigates the impact of various factors on the CO2 emissions of European trucks through vehicle simulations performed in VECTO. The chosen vehicles represent average 2015 vehicles and comprised of two rigid trucks (12 t and 18 t) and two tractor trailers (30 t and 40 t), which were simulated under their reference configurations and official driving cycles. The effects of aerodynamics, auxiliary systems, curb-weight, tyre rolling resistance, engine internal losses, engine and gearbox efficiency were investigated. Results show that air drag has the highest impact on CO2 emissions, except in the case of the 12 t rigid truck and the urban delivery cycle where engine losses have a more pronounced effect. The option that presents the highest emissions decrease potential is increased engine efficiency, an observation common for all vehicles and cycles. Other factors exhibited a varying reduction potential that depended on the vehicle category and the driving cycle. Finally results demonstrate where focus should be given for improving the energy performance of trucks in view of the Commission’s future efforts to propose CO2 reduction targets for HDVs.