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This paper showcases the utilization of response surface methodology (RSM) to optimize the performance of a CO2 geothermal thermosyphon. The design parameters include the filling ratio, the flow rate of the cooling fluid and the difference between the ground and the cooling fluid inlet temperatures, while the response parameters are the heat transfer rate (Q) and effectiveness (εff). Using the RSM, two models were developed to establish correlations between input parameters and corresponding response. Overall, it is concluded from the RSM that the flow rate and the temperature difference between the ground and the heat transfer fluid inlet temperatures are the factors that have the greatest impact on Q and εff, while the filling ratio has only a slight effect on Q and no effect on εff. The maximum heat transfer rate and effectiveness achieved are 1.86 kW and 47.8%, respectively. Moreover, these optimal values are associated with different flow rate levels, indicating distinct operating regions for maximizing Q and εff within the GT system. Therefore, a multi-response optimization approach is essential to simultaneously optimize both Q and εff.