This study proposes a new method for predicting the airtightness of a building envelope by using pressure differences that naturally occur in high-rise buildings. The background and principle of the proposed method, which uses the relationship between pressure difference and airflow, are described. The proposed method was validated by applying it to a 42-storey residential building. The differential pressure generated in the building under actual climatic conditions was measured twice during the winter season. Based on the measured pressure difference data, the airtightness of the building envelope was predicted, and those predicted values were compared with detailed measurements taken using the blower door test method. The results show that the difference between the predicted and directly measured airtightness of the building envelope for the upper floors (36th and 42nd floors), where the differential pressure was relatively large, did not differ significantly. Where the differential pressure across a building component formed by the indoor/outdoor temperature difference, the building height, and the distance from the neutral plane of the analyzed building was more than 50 Pa, the results predicted using the method proposed in this study were valid.