Purpose <p>Oxygen desaturation index (ODI) has a significant correlation with the development and progression of cardiovascular diseases (CVD) in patients with obstructive sleep apnea (OSA). Continuous positive airway pressure therapy (CPAP) improves the hypoxic burden in OSA but has not been shown to reduce cardiovascular morbidity conclusively. We evaluated if optimal CPAP titration aimed at reducing the apnea–hypopnea index (AHI), also optimally reduced the hypoxic burden, as assessed using ODI.</p> Methods <p>This was a retrospective observational study in 40 patients of OSA who underwent a split-night level 1 sleep study and achieved optimal CPAP titration based on the AHI index. We calculated the AHI and ODI during the diagnostic portion and at the optimal CPAP titration pressure and compared the results between patients with and without CVD.</p> Results <p>55% of the patients had CVD, including hypertension, dyslipidemia, or coronary artery disease. During the diagnostic study, the AHI and ODI had significant positive correlation (<i>r</i> = 0.90, <i>p</i> = 0.001). During the CPAP titration study, despite achieving an AHI of &lt; 5 events per hour in supine REM sleep, 50% of the patients had an ODI of more than 5 events per hour. At the optimal CPAP titration pressure, the median&#xa0;ODI was significantly higher in patients with CVD (<i>p</i> = &#xa0;0.06).</p> Conclusion <p>Despite optimal CPAP titration, the hypoxic burden as evaluated using ODI was persistently higher in patients with CVD. This under-correction of the hypoxic burden despite optimal CPAP titration might contribute to the progression of CVD in OSA.</p>