Background: Ketamine is a potent sedative drug that helps to maintain upper-airway patency, due to its higher upper-airway dilator muscular activity and higher level of duty cycle, as seen in rats. However, no clinical trials have tested passive upper-airway collapsibility and changes in the inspiratory duty cycle against partial upper-airway obstruction in humans. The present study evaluated both the passive mechanical upper-airway collapsibility and compensatory response against acute partial upper-airway obstruction using three different sedative drugs in a crossover trial. Methods: Eight male volunteers entered this nonblinded, randomized crossover study. Upper-airway collapsibility (passive critical closing pressure) and inspiratory duty cycle were measured under moderate sedation with ketamine, propofol, and dexmedetomidine. Propofol, dexmedetomidine, and ketamine anesthesia were induced to obtain adequate, same-level sedation, with a BIS value of 50–70 and the OAA/S score of 2–3 and RASS score of −3. Results: The median passive critical closing pressure of 0.08 [−5.51 to 1.20] cm H O was not significantly different compared to that of propofol sedation (−0.32 [−1.41 to −0.19] cm H O) and of dexmedetomidine sedation (−0.28 [−0.95 to −0.03] cm H O) (p =.045). The median passive R for ketamine 54.35 [32.00 to 117.50] cm H O/L/s was significantly higher than that for propofol 5.50 [2.475 to 19.60] cm H O/L/s; (mean difference, 27.50; 95% CI 9.17 to 45.83) (p =.009) and for dexmedetomidine 19.25 [4.125 to 22.05] cm H O/L/s; (mean difference, 22.88; 95% CI 4.67 to 41.09) (p =.021). The inspiratory duty cycle increased significantly as the inspiratory airflow decreased in passive conditions for each sedative drug, but behavior differed among the three sedative drugs. Conclusion: Our findings demonstrate that ketamine sedation may have an advantage of both maintained passive upper-airway collapsibility and a compensatory respiratory response, due to both increase in neuromuscular activity and the increased duty cycle, to acute partial upper-airway obstruction. 2 2 2 US 2 2 2