According to the characteristics of exhaust gas of diesel engine under variable conditions, a waste heat recovery system of organic Rankine cycle was designed. Under the different evaporation pressures, the effects of azeotropic mixtures and zeotropic mixtures on the performance of waste heat recovery system of organic Rankine cycle of vehicle diesel engine in variable conditions were discussed. Combined with the practical projects, the mixtures which was the most suitable for this system was chosen. The results showed that the mean value of exergy destruction rate of the ORC system using the zeotropic mixtures R415B was 38% lower than the azeotropic mixtures R508A under variable conditions. Through the comparative analysis, the zeotropic mixtures R415B was the most suitable for the waste heat recovery system of organic Rankine cycle of vehicle diesel engine under variable conditions, the maximum net power output value was about 27.60kW.