Objectives <p>The aim of this study is to compare two definitions of hypopnea: ≥ 4% decrease in the oxygen saturation (4% criterion) vs. ≥ 3% decrease in the oxygen saturation or an arousal (3%A criterion) in the diagnosis, severity determination and potential treatment eligibility in obstructive sleep apnea (OSA).</p> Methods <p>A post-hoc secondary cross-sectional analysis was conducted using data from the Multi-Ethnic Study of Atherosclerosis (MESA) Sleep Ancillary Study cohort. Concordance between the two hypopnea criteria used to calculate the Apnea Hypopnea Index (AHI) were determined. Comparisons include diagnosis and severity of OSA and potential treatment eligibility with Continuous Positive Airway Pressure (CPAP) and tirzepatide. Subgroup analyses examined variations across demographic subgroups and supine positioning.</p> Results <p>2057 participants were analyzed; 60% (<i>n</i> = 1,235) were reclassified using the 4% criterion with a decrease in severity or loss of diagnosis as compared to the 3%A criterion. Among participants potentially eligible for CPAP therapy using the 3%A criterion, 61.3% (<i>n</i> = 791) were classified as ineligible under the 4% criterion (<i>p</i> &lt; 0.0001, Cramér’s V = 0.63). 35% (<i>n</i> = 180) of participants potentially eligible for tirzepatide under the 3%A criterion were reclassified as ineligible under the 4% criterion. Increased discordance was found in females than males (65.9% (<i>n</i> = 388) vs. 57.5% (<i>n</i> = 403), <i>p</i> = 0.0018) while supine positioning decreased discordance.</p> Conclusions <p>Use of the 4% criterion was associated with substantial differences in OSA classification and potential treatment eligibility compared with the 3%A criterion. These differences were observed across severity categories and demographic subgroups with discordance more frequent among females.</p>