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Oxygenated, low energy-density fuels have the potential to decouple the NOx-soot emissions trade-off in compression-ignition engines. Additionally, synthetic fuels can provide a pathway to reach carbon-neutral utilization of hydrocarbon-based fuels in IC engines. Oxymethylene Dimethyl Ether (OME) is one such synthetic, low energy-density fuel, derived from sustainable sources that in combination with conventional fossil fuels with higher energy content, has the potential to reduce CO2 emissions below the US and EU VI legislative limits, while maintaining ultra-low soot emissions. The objective of this work is to investigate and compare the performance, emissions and efficiency of a modern multi-cylinder diesel engine under conventional high temperature combustion (HTC) with two different fuels; 1) OME310 - a blend of 10% OME3 by volume, with conventional Ultra-Low Sulphur Diesel (ULSD), and 2) D100 - conventional ULSD in North America.