Polyoxymethylene dimethyl ether (POMDME) is a new alternative fuel that can be produced from waste biomasses and tailored through the distribution of oligomers to fit into the distillation range of diesel fuel. Since one potential advantage of alternative fuels is that they could reduce emissions also from old in-use vehicles without waiting for their replacement, we have measured and evaluated the emission performance of neat POMDME and a blend of 10% POMDME and 90% commercial diesel fuel in an old Euro-2 diesel car over the NEDC driving cycle. As compared to the reference diesel fuel, the experimental results show a significant reduction in PM emissions already with the 10% blend, i.e., −18%, and even more pronounced with the neat POMDME, i.e., −77%. With this latter the PM emission reached below the Euro 4 limit. The composition of PM was quite different for the two extreme fuels; being mostly VOF from lube oil for the neat POMDME, while mostly soot in the case of diesel fuel. Possibly due to high frequency of C-O bonds in its molecular structure, the use of the neat POMDME resulted in higher emission of CO and formaldehyde that could not be compensated by the catalytic performance of the aged oxidation catalyst (DOC) of the vehicle. The neat POMDME showed also increased NOx emissions likely due to its higher combustion temperature as found in previous experiments. The emission of HC was not significantly affected by the fuel type. In conclusion, this investigation demonstrated that the use of neat POMDME is an effective way to reduce the PM from in-use old vehicles without diesel particulate filter (DPF). However, care must be taken to ensure the maintenance of an effective DOC system to reduce the emissions of CO and aldehydes.