This paper presents a novel semi-empirical thermodynamic model for the simulation of two-phase expansion in twin-screw expanders. The model utilizes a limited number of unknown parameters, the values of which are calculated through a calibration-optimization process that exploits numerical experiments available in the literature. Two-phase expansion simulations are performed for a wide variety of operating conditions, revealing that the vapor quality at the suction port of the expander is the main factor affecting its efficiency. Increased vapor qualities at the onset of expansion lead to an increase in the expander’s efficiency because a better matching between the WF’s volume ratio and the expander’s built-in volume ratio can be achieved. The thermodynamic model is applied to assess the performance of a TFC engine operating under varying heat duties and temperatures of the heat source, indicating that a detailed analysis is necessary to conclude whether the TFC or the ORC is the optimal solution for a given application.