OBJECTIVE: /Background: This study aimed to explore the clinical, polysomnographic, and heart rate variability (HRV) characteristics of highland obstructive sleep apnea (OSA) patients receiving one-night nocturnal oxygen supplementation (NOS) and to identify factors predicting response. PATIENTS/METHODS: Thirty-four highland OSA patients living in Shangri-La were randomly assigned to receive NOS and sham oxygen in a randomized, placebo-controlled, crossover trial. Clinical assessments, polysomnography, and HRV were measured. A responder was defined as a >/=50% reduction in apnea-hypopnea index (AHI) with NOS compared with sham oxygen. RESULTS: Eighteen participants responded and 16 did not respond, with a median (interquartile range [IQR]) age of 46.5 (36.5-53.0) and 48.0 (44.3-53.3) years, respectively. The median treatment effect (95% CI) on total AHI was -23.2/h (-30.0 to -17.5) and -12.0/h (-16.6 to -7.6) in responders and non-responders (p = 0.004), with similar effects on oxygen desaturation index. The mean OAH duration was prolonged by 7 s in responders together with improved sleep quality and daytime blood pressure. The mean OAH duration at baseline predicted responses to NOS with a sensitivity and specificity of 88.9% and 68.7% (AUC 0.809) at a cut-off point of 24.9 s. Changes in HRV parameters were negatively correlated with changes in mean oxygen saturation and daytime systolic blood pressure only in responders. CONCLUSIONS: NOS significantly improved OSA severity and clinical outcomes in responders, which was related to improvements in parasympathetic activity. Highlanders with shorter mean OAH may be suitable candidates for NOS. These findings provide new information about tailored treatment strategies for highland OSA patients.