In the strive for the climate-neutral and ultra-low emission vehicle powertrains of the future, synthetic fuels produced from renewable sources will play a major role. Polyoxymethylene dimethyl ethers (POMDME or “OME”) produced from renewable hydrogen are a very promising candidate for zero-impact emissions in future CI engines. To optimize the utilisation of these fuels in terms of efficiency, performance and emissions, it is not only necessary to adapt the combustion parameters, but especially to optimize the injection and mixture formation process. In the present work, the spray break-up behavior and mixture formation of OME fuel is investigated numerically in 3D CFD and validated against experimental data from optical measurements in a high pressure/high temperature chamber using Schlieren and Mie scattering. For comparison, the same operating points using conventional diesel fuel were measured in the optical chamber, and the CFD modeling was optimized based on these data. To model the spray-breakup phenomena reliably, the primary break-up model according to Fischer is used, taking into account the nozzle internal flow in a detailed calculation of the disperse droplet phase. As OME has not yet been investigated very intensively with respect to its chemico-physical properties, chemical analyses of the substance properties were carried out to capture the most important parameters correctly in the simulation. With this approach, the results of the optical spray measurement could be reproduced well by the numerical model for the cases studied here, laying the basis for further numerical studies of OME sprays, including real engine operation.