With the ESE module of FIRE software, this paper establishes the diesel engine model of 4100, and verifies the correctness with the test result. Based on this, the paper carries on a simulation on three high proportions of DME-diesel D65, D75 and D85, and makes a contract with diesel on the mean pressure, mean temperature, mass fraction, accumulated heat release, as well as the mass fraction of NOx and soot. The result shows that the higher proportional, the lower mean pressure in-cylinder. Also the result shows that NOx growth will come to a “freezing period” when it comes to a certain temperature, while soot growth is growing first and oxygenated later, and with the increase of DME proportion, NOx grows later and its mass fraction is lower. Besides, the mass fractions of soot of three kinds of mixed fuels are far below diesel’s, D85’s is the lowest.