Abstract: Objective To assess the effectiveness of the combination of supplemental oxygen and eszopiclone in obstructive sleep apnea hypopnea syndrome (OSAHS) patients whose upper airway anatomy are not severely compromised. Methods Sixty cases (critical closing pressure ≤ 5 cm H₂O, age<65 years old, 1 cm H₂O=0.098 kPa) were screened out from patients diagnosed with mild to moderate OSAHS in our hospital from August, 2015 to August, 2017. The patients were randomly divided into the treatment group and control group, 30 cases in each group. The treatment group received the combination therapy of eszopiclone (2 mg) and oxygen (2 L/min), while the control group received placebo and sham air.Sleep monitoring data including apnea hypopnea index (AHI), the longest apnea time and the lowest nocturnal oxygen saturation (SaO₂) and respiratory mechanics indexes including ventilation that caused an arousal, active collapsibility, arousal threshold and loop gain were compared in two groups before and after 3 weeks of treatment. Wilcoxon rank sum test was used to evaluate the differences between two groups. Results After 3 weeks of treatment, the AHI and the longest apnea time in the treatment group was much lower than that in the control group (Z=-3.992 and Z=-4.805, P<0.001), and the lowest nocturnal SaO₂ in the treatment group was much higher than that in the control group (Z=-6.621, P<0.001). Meanwhile, the ventilation that caused an arousal was much lower than that in the control group (Z=-6.641, P<0.001) and the arousal threshold in the treatment group was much higher than that in the control group (Z=-6.303, P<0.001), the loop gain in the treatment group was reduced more greatly than that in the control group (t=-4.934, P<0.001). Conclusion The combination of supplemental Oxygen and eszopiclone has reliable curative effect on OSAHS in selected individuals, which can improve the severity of apnea and hypopnea, ventilation that causes an arousal, arousal threshold and loop gain in those patients with a mild upper airway collapsibility. The combining targeting therapy may be an effective treatment option in selected OSAHS individuals.