Obstructive sleep apnea (OSA) is a heterogeneous disease with varying phenotype. A cluster analysis based on multidimensional disease characteristics, including symptom, anthropometry, polysomnography (PSG), and craniofacial morphology, in combination with auto-continuous positive airway pressure (CPAP) titration response and comorbidity profiles was performed within a well-characterized cohort of patients with OSA, with the aim to refine current phenotypic expressions of OSA with clinical implications.Two hundred and ninety-one subjects with a new diagnosis of moderate to severe OSA, referred for auto-CPAP titration to the sleep center were included for analysis. In-laboratory PSG and craniofacial computed tomography (CT) scanning was performed, followed by an auto-CPAP titration. The symptom of excessive daytime sleepiness (EDS) was assessed by Epworth sleepiness scale (ESS).Three patient phenotypes, corresponding to the "normal weight, non-sleepy and moderate OSA", the "obese, non-sleepy and severe OSA" and "obese, sleepy, very severe OSA with craniofacial limitation" were identified. Among the PSG parameters, only N3% and mean pulse oxygen saturation (SPO2) were found to be associated with ESS, and they only explain small fraction of the variation (R2=0.136). Neck circumference and craniofacial limitation were associated the more severe phenotype, which had higher prevalence of hypertension, metabolic syndrome, greater diurnal blood gas abnormalities and worse PAP titration response.Three OSA phenotypes were identified according to multiple aspect of clinical features in patients with moderate to severe OSA, which differed in prevalence of hypertension, metabolic syndrome, diurnal blood gas parameters and CPAP titration response. Self-reported EDS was not related with the severity of sleep breathing disturbance, and craniofacial limitation was associated the more severe phenotype. These findings highlight the necessity of integrate multiple disease characters into phenotyping to achieve better understanding of the clinical pictures of OSA.© 2022 American Academy of Sleep Medicine.