Hybrid ventilation is an effective approach to reduce cooling energy consumption by combining natural and mechanical ventilation. Previous studies of full-scale whole-building measurements of high-rise hybrid ventilation are quite limited due to the complexities of buildings and variable ambient conditions. As a result, validated and accurate whole-building simulations of hybrid ventilation often cannot be found in the literature. This paper reports a series of full-scale measurements of hybrid ventilation in a 17-storey high-rise building and associated whole-building simulations by 15-zone detailed and a 5-zone simplified multizone models. The paper is one of the first studies of using multizone models and real-world full-scale data and sharing key operational and performance experience and case studies of high-rise hybrid ventilation. Both the test data and the validated simulation models can be used for the comparison and validation of simulation models. The 5-zone simplified model developed from this study was able to model such a complex high-rise building by only a few zones, making possible the on-line model predictive control of a high-rise building. This was illustrated in this paper by an example of optimizing the uniformity of the hybrid ventilation on different floors by modifying inlet areas.