BACKGROUND: Interferon (IFN) is widely used in clinical practice and nebulization inhalation is one of the commonly used routes of administration. However, nebulization drugs such as interferon-α (IFN-α) with large molecular weights may deposit in the membrane of the breathing filters, causing its resistance to gradually increase. Thus, our study explores the effect of IFN-α and other nebulization drugs on the resistance of breathing circuit filters under invasive mechanical ventilation. METHODS: We divided 96 breathing filters into eight groups. The baseline group was not treated while the blank group was installed but were not nebulized. The remaining groups received jet nebulized or vibrating nebulized with either normal saline, Combivent, Amphotericin B, or IFN-α at a frequency of once every 12 hours separately and were removed from the breathing circuit after 24 hours. The resistance of the filter of each group was then measured and statistical comparisons were made. RESULTS: Filter resistance of the IFN-α jet nebulization group was greater than that of the other groups, and there were statistical differences except for the Amphotericin B jet nebulization group. Comparison of the resistance [cmH(2)O/(L·s)] of the IFN-α jet nebulization group vs. the baseline group showed 2.56 (2.40, 2.68) vs. 2.26 (2.03, 2.40), P=0.037; of the IFN-α jet nebulization group vs. the blank group showed 2.56 (2.40, 2.68) vs. 2.11 (1.98, 2.27), P=0.003; of the IFN-α jet nebulization group vs. the normal saline group: 2.56 (2.40, 2.68) vs. 2.16 (2.08, 2.32), P=0.023; of the IFN-α jet nebulization group vs. the Combivent jet nebulization group: 2.56 (2.40, 2.68) vs. 2.18 (2.14, 2.27), P=0.018; and of the IFN-α jet nebulization group vs. the Amphotericin B jet nebulization group: 2.56 (2.40, 2.68) vs. 2.33 (2.05, 2.45), P=0.221. The effect of jet nebulization and vibrating mesh nebulization on the resistance of breathing filters showed no significant statistical difference. CONCLUSIONS: Jet nebulization with IFN-α significantly increased the resistance of the breathing filter within 24 hours and there was no significant difference in filter resistance between jet nebulization and vibrating mesh nebulization of IFN-α or Amphotericin B.