Study objectives: To study the pattern of upper airway collapse in patients with CPAP failure by performing DISE while administering CPAP therapy and to determine the reason for CPAP failure accordingly. Methods: This observational retrospective study comprised 30 patients diagnosed with OSA and CPAP failure, who underwent DISE while administering CPAP therapy. During DISE, the upper airway was assessed with and without CPAP therapy using the VOTE classification. Additionally, a jaw thrust maneuver was performed, in order to mimic the effect of an additional mandibular advancement device (MAD) in combination with CPAP therapy. Consequently, the outcome of DISE was translated into a clinically relevant categorization. Results: Eleven patients (37%) had a persistent anteroposterior (AP) collapse, including a collapse at velum, tongue base, or epiglottis level and multilevel collapse. Eight patients (27%) had a floppy epiglottis. Five patients (17%) had a persistent complete concentric collapse (CCC) and three patients had a persistent laryngeal collapse (10%). In three patients (10%), no airway collapse was found after CPAP administration. Conclusions: Based on the results of the reported study, in most cases, the potential cause of CPAP failure can be determined by this new diagnostic method. Consequently, suggestions can be made for additional therapy.