A comparative analysis between Rayleigh damping model and Caughey damping model was first conducted, and then, by ANSYS secondary developing based on APDL programming language, the Caughey damping model was successfully applied to the random seismic response analysis of complex high-rise building structure. An actual complex high-rise building structure was selected as the research object. By using the combination method of field vibration test and numerical simulation, the influence of different damping models on the random seismic response of complex high-rise building was analyzed, and the applicability and effectiveness of the two damping models were also discussed. The results have indicated that the curve shape of Rayleigh damping model is closely related to the control frequencies, the calculated damping ratio is lower than the actual test damping ratio between two control frequencies, and it is contrary among other frequency ranges. The Caughey damping model can more accurately meet the actual damping in a wider frequency range.