The increasing CO2 concentration in the atmosphere and the resulting climate change require an immediate and efficient reduction of anthropogenic carbon-dioxide emission. This target can be achieved by the usage of CO2-neutral fuels even with current technologies (Schemme et al. in Int J Hydrogen Energy 45:5395–5414, 2020). Diesel engines in particular are amongst the most efficient prime movers. Using oxymethylene-dimethyl-ether (OME) it is possible to solve the hitherto existing Soot-NOx-Trade-off. OME has bounded oxygen in the molecular chain. This reduces the formation of soot, but equally the calorific value. But in considerance of the physical and chemical properties of OME, it could be useful to optimize the standard diesel engine into an OME engine. As a result, single-cylinder tests were performed to obtain a detailed analysis of the differences between OME3-5 and commercially available DIN EN 590 Diesel. Based on the fact that OME has gravimetrically less than half the calorific value of diesel, twice the fuel mass must be injected for the same energy release in the combustion chamber. Therefore, at the beginning of the investigations, a variation of the injector flow rate was carried out by means of different nozzle hole diameters. The evaluation of the results included the fundamental differences in the combustion characteristics of both fuels and the determination of efficiency-increasing potentials in the conversion of OME3-5. Due to the lower ignition delay and the shorter combustion time of OME, potentials in the optimisation of the injection setting became apparent. Higher energy flows over the combustion chamber wall were noticeable in operation with OME. To get to the bottom of this, the single-cylinder investigations were supported by tests on the optically accessible high-pressure chamber and the single-cylinder transparent engine. The optical images showed a narrower cone angle and greater penetration depth of the OME injection jet compared to the diesel injection jet. This confirmed the results from the single-cylinder tests. This provides further potential in the design of the injector nozzle to compensate for these deficits. Overall, this work shows that operation with OME in a classic diesel engine is possible without any significant loss in efficiency and with little effort in the hardware. However, it is also possible to achieve more efficient use of the synthetic fuel with minor adjustments.