The well-known problem of reduced drug delivery that occurs when heated, humid air is used with pressurized metered-dose inhalers (pMDIs) and spacers in intubated settings is carefully studied with Airomir using an in vitro model under controlled conditions of temperature and humidity. A better understanding of the physical processes leading to the aforementioned drop in performance is obtained, and a method is devised to circumvent the problem without having to reduce the temperature or humidity of the ventilator circuit. The present study shows that the mole fraction of water vapor in the ventilation air (and not the temperature) is the major factor behind the sharp drop in the amount of drug delivered to the lung. However, the presence of water vapor does not affect performance because of hygroscopic growth. Instead, it influences the initial atomization process and the early stages of aerosol generation. Removal of these negative effects can be achieved by using a larger spacer that allows longer times for the aerosol to evaporate, as is demonstrated in the present study.