To estimate the ventilation rate of buildings, the orifice equation with a fixed discharge coefficient (Cd) is often applied. However, values of Cd may be not a constant for the openings of naturally-ventilated dairy buildings. The main objective of this study was to investigate the influence of the building configurations on the Cd value. In addition, since the value of the pressure difference across the opening is crucial to the application of the orifice equation, another objective was to evaluate the accuracy of using the orifice plate method in pressure difference measurements. The investigations were carried out using computational fluid dynamics simulations. The results showed that applying the orifice plate method to measure the pressure drop could result in up to 18.9% relative error in estimates of Cd for the case with an opening ratio of 81.4%. Additionally, the value of Cd was found to be dependent on the opening ratio, the inlet opening position, and the inlet-to-outlet area ratio, but it was independent of the outlet opening position and the roof slope. It can be concluded that the Cd value should be specified according to the opening configurations in the application of the orifice equation.