The use of CO2-neutral synthetic fuels in internal combustion engines contributes to achieving climate targets. Since their combustion is still associated with pollutant emissions, current research is focusing on minimizing harmful emissions, as well as on improving the efficiency of the combustion. The soot-free combustion of the synthetic diesel fuel oxymethylene ether (OME) opens up new scopes for reducing the remaining pollutants, particularly nitrogen oxides (NOX). Catalytic aftertreatment of NOX is costly and may lead to the generation of further emissions such as nitrous oxide, making it necessary to further investigate engine-internal approaches of NOX reduction. This work shows the influence of various in-engine measures on emissions and efficiency for OME and hydrogenated vegetable oil (HVO) as paraffinic diesel fuel, performed on a 1.75 l single-cylinder research engine. An injector variation was carried out for OME to compensate for the reduced lower heating value by a higher nozzle flow rate, which increases efficiency, but also NOX emissions. The examination of the measures of increasing exhaust gas recirculation, lowering rail pressure, Miller valve timing and high compression ratio shows a significant reduction in nitrogen oxide emissions in each case. At the same time, there is an improvement in indicated efficiency for Miller valve timing and high compression ratio, and with OME, in contrast to HVO, also by reducing the rail pressure. With HVO, each measure increases particulate number by up to several orders of magnitude. For OME, none of the measures resulted in a deterioration of the low particulate emissions, which allows an intensified application and combination of the measures. For example, the simultaneous application of higher compression, early intake closing and decreased injection pressure reduces nitrogen oxide emissions by more than two-thirds and improves efficiency by 5% without increasing particulate emissions.