Propofol (P) and midazolam (M) are frequently given by continuous infusion for sedation in critically ill, mechanically ventilated patients. We compared these drugs with regard to: (1) time-to-awaken; (2) reproducibility of bedside assessments of level of sedation; (3) time-to-sedation; and (4) change in oxygen consumption (V O2) from awake to sedated state. Seventy-three patients were prospectively randomized to receive either P (n=37) or M (n=36). Wake-up times after stopping the drug were assessed by blinded and unblinded observers, by asking patients to perform simple tasks. Times to sedate were assessed by consensus agreement among nurses and investigators. Demographics and APACHE II scores were not different between P and M. The P group had a significantly narrower range of wake-up times with a higher likelihood of waking in less than 60 min. Blinded versus unblinded observations had excellent correlation. Average time to sedate and decrease in V O2 were not different. We conclude that in this patient population: (1) both P and M achieved optimal sedation in a large fraction of patients when administered by specified dosing protocols; (2) P had a faster, more reliable, wake-up time; (3) assessments of time-to-awaken were objective and reproducible; (4) time to sedation was not significantly different; (5) V O2 decreased similarly with both.