Purpose: Mechanical ventilation (MV) is one of the most important treatment to achieve sufficient alveolar ventilation in patients with lack of adequate pulmonary gas exchange. This study was performed to evaluate the effects of tidal volume ventilation to diaphragmatic dysfunction by both histological evaluation and the main protease pathway after MV with a murine ventilator induced diaphragmatic dysfunction (VIDD) model. Materials and Methods:Healthy male C57/BL6 mice (10 - 12 weeks old, 25 - 30 g) were randomly divided into 3 experimental groups: high tidal volume MV for 6 hours (HTV group, n = 6), low tidal volume MV for 6 hours (LTV group, n = 6), and control (Control group, n = 6). Arterial blood gas analysis, examination of diaphragmatic contractile properties, histological evaluation, and biochemical evaluation of main proteolysis pathways were performed in all three groups. Results:The results of arterial blood gas analysis were comparable among the three groups and all of them were within the normal ranges. Diaphragmatic force production was lower in the HTV group compared to the LTV and control group, respectively. Diaphragmatic force production in the LTV group was higher than that in the HTV group but only slightly reduced compared to the control group. There were no histological differences were found between the groups. No alterations in the level of calpain 1 or 2 were observed among the group, respectively. Conclusion:Lower tidal volume ventilation partially reduces ventilator-induced diaphragmatic dysfunction. Further studies are needed to determine the mechanism.