Natural ventilation can provide building occupants with thermal comfort and a healthy indoor environment. Among all the design related parameters that affect ventilation performance, ventilation mode (i.e. single-sided and cross ventilation) is perhaps the main one. The current study uses full-scale in-situ measurements to investigate the effect of ventilation mode on thermal comfort and ventilation performance of a high-rise case study unit. Two modes of natural ventilation, single-sided and cross ventilation, are investigated. Air velocity, temperature and relative humidity were measured for both ventilation modes on two consecutive days in summer. Indoor thermal conditions were evaluated using the extended Predicted Mean Vote (PMV) and Standard Effective Temperature (SET*) comfort models. In addition, the relationship between reference wind speed and internal airflow, airflow distribution, and the effect of wind direction on internal airflow were investigated for both single-sided and cross ventilation. Finally, the implications of the research outcomes on natural ventilation design are discussed. Indoor thermal conditions were found to be within the comfort zone for more than 70% of the time under cross ventilation operation while single-sided ventilation provided adequate thermal conditions for only 1% of the time. Results from this study highlight a significantly better performance of cross ventilation over single-sided ventilation. (C) 2017 Elsevier B.V. All rights reserved.