Zeotropic mixture-based organic Rankine cycle (ORC) is a promising technology for harvesting engine waste heat as the property called temperature glide can efficiently improve the temperature mismatch between working fluid and varying temperature heat source. However, a phenomenon called composition shift appearing as different fractions between circulating composition and charge composition accompanies in zeotropic mixtures-based ORC system, which affects system performance directly. To investigate the influence of composition shift on system performance, this paper establishes the thermodynamic model and composition shift model of ORC system. On the basis of simulation results for selected alkanes/R123 zeotropic mixture, the circulating fraction of R123 is higher than its charge fraction, which results in a lower performance of ORC system. For cyclohexane/R123 mixture, the actual mass fraction of R123 increases from 0.5 to 0.52, leading to a maximum decrease of net power by 3%. The factors affecting composition shift such as charge fraction, evaporation pressure, and charge quality are discussed. By increasing the charge fraction of R123, the composition shift can be alleviated within the limitation of safety boundary in this paper. Higher evaporation pressure and larger charge quality can also mitigate the composition shift. Besides, the results indicate that composition shift and temperature glide have similar changing trends, thus temperature glide could be used as predicting the degree of composition shift.