The purpose of this study was to evaluate and compare the clinical effects, safety, and economic cost of propofol and midazolam in the sedation of patients undergoing mechanical ventilation in the ICU. Eighty-eight critically ill patients were studied and randomly allocated to receive short-term (less than 24 h), medium-term (24 h to 7 days), and prolonged (more than 7 days) continuous sedation with propofol (n = 46) or midazolam (n = 42). Mean doses required were 2.36 mg/kg/h for propofol and 0.17 mg/kg/h for midazolam. Patients in the group receiving propofol showed a percentage of hours of sedation at the desired level (grade 2, 3, 4, or 5 on the Ramsay scale) of 93 percent, compared with 82 percent (p < 0.05) in the group receiving midazolam. Both agents were considered safe with respect to the induction of adverse reactions during their use in prolonged sedation. Recovery after interrupting sedation was significantly faster in patients treated with propofol than in those sedated with midazolam (p < 0.05). Recovery of total consciousness was predictable according to sedation time in propofol-treated subgroups (r = 0.98, 0.88, and 0.92, respectively), while this correlation was not observed in the midazolam-treated group. In the subgroup with sedation of less than 24 h, propofol provided a cost savings of approximately 2,000 pesetas (pts) per patient, due to shorter stays in the ICU. We conclude that propofol is a sedative agent with the same safety, higher clinical effectiveness, and a better cost-benefit ratio than midazolam in the continuous sedation of critically ill patients.