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The present work demonstrates a comparative study of hydrogen fuel cells and combustion aircraft to investigate the potential of fuel cells as a visionary propulsion system for radically more sustainable medium- to long-range commercial aircraft. The study, which considered future airframe and propulsion technologies under the Se2A project, was conducted to quantify potential emissions and costs associated with such aircraft and to determine the benefits and drawbacks of each energy system option for different market segments. Future technologies considered in the present work include laminar flow control, active load alleviation, new materials and structures, ultra-high bypass ratio turbofan engines, more efficient thermal management systems, and superconducting electric motors. A multi-fidelity initial sizing framework with coupled constraint and mission analysis blocks was used for parametric airplane sizing and calculations of all necessary characteristics. Analyses performed for three reference aircraft of different sizes and ranges concluded that fuel-cell aircraft could have operating cost increases in the order of 30% compared to hydrogen combustion configurations and were caused by substantial weight and fuel burn increases. In-flight changes in emissions of fuel cell configurations at high altitudes were progressively reduced from medium-range to long-range segments from being similar to hydrogen combustion for medium-range to 24% for large long-range aircraft, although fuel cell aircraft consume 22–30% more fuel than combustion aircraft. Results demonstrate a positive environmental impact of fuel cell propulsion for long-range applications, the possibilities of being a more emission-universal solution, if desired optimistic technology performance metrics are satisfied. The study also demonstrates progressively increasing technology requirements for larger aircraft, making the long-range application's feasibility more challenging. Therefore, substantial development of fuel cell technologies for long-range aircraft is imperative. The article also emphasizes the importance of airframe and propulsion technologies and the necessity of green hydrogen production to achieve desired emissions. [ABSTRACT FROM AUTHOR]