A new approach of NOx reduction in the compression-ignition engine is introduced in this work. The previous research has shown that during the combustion stage, the high temperature ignition tends to occur early at the near-stoichiometric region where the combustion temperature is high and majority of NOx is formed; Therefore, it is desirable to burn the leaner region first and then the near-stoichiometric region, which inhibits the temperature rise of the near-stoichiometric region and consequently suppresses the formation of NOx. Such inverted ignition sequence requires mixture with inverted phi-sensitivity. Fuel selection is performed based on the criteria of strong ignition T-sensitivity, negligible negative temperature coefficient (NTC) behavior, and large heat of vaporization (HoV). Based on the suggested criteria, Ethanol (C2H5OH) is selected as the preliminary test fuel for this study. 0-D ignition delay analysis is performed to illustrate the selected fuel’s potential to generate mixture with inverted phi-sensitivity. 3-D engine CFD simulation is conducted with the selected fuel under different engine load conditions. The inverted phi-sensitivity and the inverted ignition sequence are demonstrated to exist in the engine simulation. The NOx reduction by inverted ignition sequence is effective at low and medium load. At high load, the proposed method fails to reduce the NOx emission due to the high overall equivalence ratio.