Background: Daily interruption of continuous infusion of sedatives has improved outcomes in patients receiving mechanical ventilation in open-label studies. Objectives: To assess the feasibility of a protocol for a doubleblind, randomized, controlled trial study on the impact of routine daily interruption of sedation in patients receiving mechanical ventilation. Methods: A total of 50 patients receiving mechanical ventilation were randomized to daily interruption of fentanyl and/or midazolam infusions for up to 6 hours or to usual management of sedation. Blinding was achieved by using replacement infusions (saline or active drug in saline). Results: The recruitment target of 80 patients was not met in an extended time frame. Propofol was used outside the protocol in 27% of patients in the intervention group and 17% of patients in the control group (P = .10). A total of 15% of the intervention group and 12% of the control group never had replacement infusions started (P = .77), and replacement infusions were started on only approximately one-third of eligible days in patients who received replacement infusions.The mean doses of fentanyl and midazolam were similar. The blinding strategy was safe and effective: no patients had unplanned extubations, and the most frequent reason for ending replacement infusions was completion of the maximum 6-hour period. Conclusions: The double-blinded design for assessment of sedation interruption in patients receiving mechanical ventilation was safe and effective. Slow recruitment of patients and frequent noncompliance with the protocol suggest that modifications to the protocol are needed.