Background: The risk of cardiovascular diseases is known to be increased in obstructive sleep apnea (OSA), the mechanism of which can be explained by the observation that the sympathetic tone increases during sleep due to repetitive apnea accompanied by hypoxia and arousal. Heart rate variability (HRV) represents the cardiac autonomic function and is mediated by respiratory sinus arrhythmia, baroreflex-related fluctuation, and thermoregulation-related fluctuation. The aim of the present study was to determine whether treatment by continuous positive airway pressure (CPAP) or O2 could produce significant changes in HRV, especially in the time domain of HRV (SDNNs and RMSSDs), in patients with OSA. Method: Fifty-seven patients with OSA were participated in the current single-center randomized parallel-group clinical trial study. The patients were randomly divided into 2 groups: the CPAP group and the O2 therapy group. Before treatment, the apnea-hypopnea index (AHI) was measured by polysomnography in each patient. HRV was assessed via 24-hour Holter monitoring, before and after 2 weeks of CPAP titration or O2 therapy, and subsequently compared between the 2 groups. The Wilcoxon test and the T-test were used for the statistical analyses. Results: Our results demonstrated a reduction in the nocturnal SDNNs (P < 0.001) and RMSSDs (P = 0.001) and an elevation in the diurnal RMSSDs significantly (P = 0.04) following CPAP. In addition, O2 therapy reduced the diurnal SDNNs significantly (P = 0.01) and elevated the nocturnal RMSSDs (P < 0.001). Conclusions: Our findings demonstrated that CPAP was an effective treatment in comparison with O2 therapy in improving HRV in our patients with OSA. Furthermore, correction of hypoxia by using nocturnal O2 therapy was not sufficient to improve HRV indices. (Iranian Heart Journal 2017; 18(4):34-41)