Objective To investigate the clinical significance of lateral position ventilation in the treatment of invasive ventilation in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Methods From October 2014 to December 2016, 60 eligible patients with AECOPD who meeting the inclusion criteria were randomly assigned to an intervention group (n=30) or a control group (n=30). Expectorant, antiasthmatic, anti-infective, invasive ventilation, bronchoscopy, analgesic sedation, invasive-noninvasive sequential ventilation, nutritional support, intensive care and other treatment were conducted in two groups, but lateral position ventilation was subsequently performed in the intervention group and the control group used half lateral position. Outcome measurements included pH, PaO2/FiO2, arterial partial pressure of carbon dioxide (PaCO2), heart rate (HR), respiratory rate (R) and air way resistance (Raw) before and one day after invasive ventilation, and duration of control of pulmonary infection (PIC), invasive mechanic ventilation (IMV), mechanic ventilation (MV) and intensive care unit (ICU) stay. Results Compared with before ventilation, the levels of PaO2/FiO2, PaCO2, HR, R and Raw were significantly changed in two groups after ventilation (P<0.05). One day later after ventilation, pH [interventionvs. control: (7.43±0.07) vs. (7.37±0.11)], PaO2/FiO2[(253.52±65.33) mm Hg (1 mm Hg=0.133 kPa) vs. (215.46±58.72) mm Hg] and PaCO2 [(52.45±7.15) mm Hg vs. (59.39±8.44) mm Hg] were statistically significant (P<0.05), but no significant difference was found in HR, R or Raw between two groups (P>0.05). Compared with the control group, PIC [(3.7±1.4) daysvs. (5.3±2.2) days], IMV [(4.0±1.5) days vs. (6.1±3.0) days], MV [(4.7±2.0) days vs. (7.3±3.7) days] and ICU stay [(6.2±2.1) days vs. (8.5±4.2) days] were significantly decreased (P<0.05) in the intervention group. Conclusions In AECOPD patients, invasive ventilation using lateral position ventilation can significantly improve arterial blood gas index, decrease Raw, shorten the time of PIC, IMV, MV and ICU stay.