BACKGROUND: Humidification is a standard of care during invasive mechanical ventilation. Two types of devices are used for this purpose: heated humidifiers and heat-and-moisture exchangers (HME). AIM: To compare the short-term physiologic effects of an active HME, with those of heated humidifiers and HMEs in terms of respiratory effort, ventilatory pattern, and arterial blood gases during invasive mechanical ventilation. METHODS: We conducted a randomized crossover study with 3 different devices in 15 stable subjects who had a tracheostomy and were ventilator-dependent. Transdiaphragmatic pressure, ventilatory pattern, arterial blood gases, and dyspnea scale were recorded at baseline and at the end of a 20-min period with each device. RESULTS: Compared with heated humidifiers, the active HME was associated with higher diaphragmatic pressuretime product per minute (117.10 [interquartile range {IQR} 34.58-298.60]) versus 80.86 (IQR, 25.46-110.55) cm H 2 O؋s/min, P ؍ .01), higher P aCO 2 (48.50 [IQR, 40.65-53.70] vs 39.60 [IQR, 37.50-49.95]) mm Hg, P ؍ .02) and lower pH (7.41 [IQR, 7.36-7.49] vs 7.45 [IQR, 7.40-7.51], P ؍ .030) without any significant difference in ventilatory pattern. A significantly worse dyspnea scale score (active HME, 3 (2-4) vs heated humidifiers: 4 (3-5); P ؍ .009) was also observed. No significant differences were seen between active HME and HME. CONCLUSIONS: This study indicated that, compared with the heated humidifiers, the use of the active HME or the HME increased inspiratory effort, P aCO 2 , pH, and dyspnea in stable subjects who were tracheostomized and ventilator-dependent. (ClinicalTrials.gov registration NCT02499796.