A simplified macroscopic method is commonly used for wind-driven ventilation analysis of buildings with small openings. Consequently, it is reasonable to question if and under what conditions will this method provide accurate results in predicting ventilation flow rates in buildings with large openings. We investigate a single-zone cubic building with two equal large openings using a computational fluid dynamics approach. We analyzed the driving forces and the ventilation flow rates due to wind as a function of the geometry, size and relative location of the two openings. The ventilation flow rates are found to be affected by both wind flows around and through the building when the two openings are relatively large. The simplified macroscopic method can provide reasonable engineering accuracy (i.e., less than 10% error) when the porosity of the building envelope does not exceed a critical value. This critical value is not a constant; instead it depends significantly on the degree of alignment between the wind direction and the character of the dominant stream tube associated with the flow through the room. We found that the simplified macroscopic method fails to provide acceptable accuracy when this stream tube is truly dominant and parallel to the wind direction. The effects of wall thickness and aspect ratio of openings are also investigated.