Background <p>Obstructive sleep apnea (OSA) is a heterogenous disease with several pathophysiological phenotypes; therefore, treatment must be tailored accordingly. This study aimed to explore the therapeutic effects of oxygen (O₂) inhalation in OSA patients with high carotid body (CB) chemosensitivity (hCBC).</p> Methods <p>CB chemosensitivity (CBC) was measured with the Dejours test in this single-arm clinical trial, and hCBC was defined as a respiratory rate reduction of &gt; 12% after inhalation of pure O₂. Subjects with hCBC were enrolled for two overnight polysomnographies, the first one with air inhalation and the second one with O₂ inhalation.&#xa0;The morning blood pressure after awakening was measured along with heart rate variability (HRV) metrics, including high-frequency power (HF), low-frequency power (LF), and the LF/HF ratio.</p> Results <p>A cohort of 74 OSA patients exhibiting hCBC were enrolled. The mean CBC, as measured by the Dejours test, was 17.4 ± 4.2%. The apnea–hypopnea index (AHI) was significantly lower when the patients inhaled O₂ (19.92 ± 13.49 events/h) compared to when they inhaled air (26.53 ± 12.18 events/h; <i>P</i> = 0.003). O₂ inhalation also improved the nadir pulse O₂ saturation (SpO₂) (75.81 ± 12.44% vs. 83.91 ± 6.97%, <i>P</i> = 0.0021), decreased the blood pressure in the morning from 107.3 ± 8.32&#xa0;mmHg (air inhalation) to 94.08 ± 5.93&#xa0;mmHg (O₂ inhalation), and lowered the HRV, as demonstrated by changes in the natural logarithm-transformed values of LF (8.933 ± 1.472 ln ms² vs. 6.231 ± 2.136 ln ms², <i>P</i> &lt; 0.001), and the LH/HF ratio (1.381 ± 0.431 vs. 1.124 ± 0.319, <i>P</i> = 0.025).</p> Conclusion <p>O₂ inhalation decreased symptom severity in OSA patients with hCBC as well as alleviated cardiovascular complications related to OSA.</p>