Objective To observe the effect of low tidal volume mechanical ventilation on outcomes of children with severe hand foot mouth disease (HFMD) complicated with neurogenic pulmonary edema (NPE). Methods 80 children with HFMD complicated with NPE were randomly divided into control group and observation group, 40 children in each group. The control group was given conventional tidal volume (10~12ml/kg) mechanical ventilation while the observation group was given low tidal volume (6~8ml/kg) mechanical ventilation. Blood gas analysis indexes pH, arterial partial pressure of oxygen (PaO₂), partial pressure of carbon dioxide (PaCO₂), time of ventilation, time of oxygen inhaling, length of ICU stay, hospitalization time, incidence of complications and long-term outcome were compared between the two groups after 24h of mechanical ventilation. Results After 24h of mechanical ventilation, the pH of observation group was significantly lower than that of control group (P<0.05), and the PaCO₂ in observation group was significantly higher than that in control group (P<0.05). There was no significant difference between the two groups in PaO₂ (P>0.05). The time of ventilation, time of oxygen inhaling, length of ICU stay and hospitalization time of observation group were significantly shorter than those of control group (P<0.05). The incidence of ventilator associated lung injury (VALI) and the conversion rate of critical illness in observation group were obviously lower than those in control group (P<0.05). The long-term outcome of observation group was better than that of the control group (P<0.05). Conclusion The application of low tidal volume mechanical ventilation in children with HFMD complicated with NPE helps to shorten the time of mechanical ventilation and length of ICU stay, and reduce the incidence of VALI and conversion rate of critical illness.