Introduction: The use of heat moisture exchangers (HMEs) is becoming more popular with many institutions delivering aerosolized medications between the HME and the endotracheal tube of patients being mechanically ventilated. When HMEs become saturated resistance can increase which can cause changes that can lead to patient-ventilator dysnchrony, development of intrinsic PEEP, and weaning difficulty. The purpose of this study was to determine the effects of aerosol drug delivery on resistance through heat-moisture exchangers. Method: An in-vitro model to simulate exhaled heat and humidity from a patient’s lungs was developed by connecting the test lung to a cascade humidifier that was placed between the endotracheal tube and the test lung. Temperature (37 ºC) and relative humidity (100%) were held constant through all test runs. Ventilator settings used for the study were as follows: Tidal volume 500 mL, frequency 15/min, PEF 60 L/min, PEEP 5 cmH2O, bias flow 2 L/min and I:E ratio 1:3.The pressurized metered-dose inhaler (pMDI; ProAir HFA) with a minispacer (Thayer Medical), hand-held nebulizer (HHN; Salter Labs) and placebo (No aerosol generator or medication) were compared. Albuterol sulfate (2.5 mg/3 ml) was administered through continuous HHN and six puffs of albuterol were given from a pMDI equaling one treatment. Neither medication nor aerosol device was used with the placebo group in order to determine the effect of HME on airway resistance during mechanical ventilation. Six aerosolized treatments were given to simulate a patient receiving albuterol every four hours over a twenty-four hour period. While five minutes was allowed between treatments, airway resistance was measured via the ventilator before and after the administration of the placebo, pMDI and HHN, which equaled five-minute intervals. Data Analysis: Descriptive statistics, dependent t-tests, one-way analysis of variance (ANOVA), repeated measures ANOVA and post-hoc multiple comparisons were utilized for the data analysis of this study, using SPSS version 16.0. A p-value<0.05 was considered significant. Results: There is a linear time effect with means of airway resistance increasing overtime not only with the placebo but also with the pMDI and nebulizer. At the end of all treatments, the means of resistance with the placebo, pMDI and nebulizer were 9.31 cmH2O/L/sec, 9.37 cmH2O/L/sec and 11.20 cmH2O/L/sec, respectively. While no significant difference was found between the placebo and the pMDI (p=0.452), the nebulizer significantly increased airway resistance when compared to placebo (p=0.004) and the pMDI (p=0.02). Conclusion: Airway resistance increases with use of the placebo, pMDI, and JN groups. Aerosol generators showed a greater increase in resistance when compared to placebo with the greater increase in resistance by HHN.