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Heavy-duty vehicles (HDVs) are responsible for a significant amount of CO2 emissions in the transport sector. The share of these vehicles is still increasing in the European Union (EU); nevertheless, rigorous CO2 emission reduction schemes will apply in the near future. Different measures to decrease CO2 emissions are being already discussed, e.g., the electrification of the powertrain. Additionally, the impact of autonomous driving on energy consumption is being investigated. The most common types are fuel cell vehicles (FCEVs) and battery-only vehicles (BEVs). It is still unclear which type of powertrain will prevail in the future. Therefore, we developed a method to compare different powertrain options based on different scenarios in terms of primary energy consumption, CO2 emissions, and fuel costs. We compared the results with the internal combustion engine vehicle (ICEV). The model includes a model for the climatization of the driver's cabin, which we used to investigate the impact of autonomous driving on energy consumption. It became clear that certain powertrains offer advantages for certain applications and that sensitivities exist with regard to primary energy and CO2 emissions. Overall, it became clear that electrified powertrains could reduce the CO2 emissions and the primary energy consumption of HDVs. Moreover, autonomous vehicles can save energy in most cases. [ABSTRACT FROM AUTHOR]