STUDY OBJECTIVES: Drug-induced sleep endoscopy (DISE) using propofol is commonly used to identify the pharyngeal structure involved in collapse among patients with obstructive sleep apnea. DISE has never been compared with zolpidem-induced sleep endoscopy. We hypothesized that propofol at recommended sedation levels does not influence upper airway collapsibility nor the frequency of multilevel pharyngeal collapse as compared with zolpidem-induced sleep. METHODS: Twenty-one patients with obstructive sleep apnea underwent polysomnography and sleep endoscopy during zolpidem-induced sleep and during DISE with propofol. A propofol target-controlled infusion was titrated to achieve a bispectral index between 50 and 70. Airway collapsibility was estimated and compared in both conditions by peak inspiratory flow and the magnitude of negative effort dependence. Respiratory drive was estimated by the difference between end-expiratory and peak-negative inspiratory pharyngeal pressure (driving pressure). Site and configuration of pharyngeal collapse during zolpidem-induced sleep and DISE with propofol were compared. RESULTS: The frequency of multilevel collapse during zolpidem-induced sleep was similar to that observed during DISE with propofol (72% vs 86%, respectively; difference: 14%; 95% confidence interval: -12% to 40%; P = .453). The endoscopic classification of pharyngeal collapse during both conditions were similar. Peak inspiratory flow, respiratory drive (effect size: 0.05 and 0.03, respectively), and negative effort dependence (difference: -6%; 95% confidence interval: -16% to 4%) were also similar in both procedures. CONCLUSIONS: In this pilot study, recommended propofol doses did not significantly increase multilevel pharyngeal collapse or affect upper airway collapsibility and respiratory drive as compared with zolpidem-induced sleep. CLINICAL TRIAL REGISTRATION: Registry: clinicaltrials.gov; Name: Natural and Drug Sleep Endoscopy; URL: https://clinicaltrials.gov/ct2/show/study/NCT03004014; Identifier: NCT03004014.