Due to the development of the automotive fuel cell systems, the study on water-injection twin screw compressor has been aroused again. Twin screw compressors with water injection can be used to supply the clean compressed air for the Proton Exchange Membrane (PEM) fuel cell systems. In this research, a thermodynamic model of the working process of water-injection twin screw compressor was established based on the equations of conservation of mass and energy. The effects of internal leakage and air–water heat transfer were taken into account simultaneously in the present mathematical model. The experiments of the performance of a prototype compressor operating under various conditions were conducted to verify the model. The results show that the predictions of the model are in reasonable agreement with the experimental data.