OBJECTIVE:: Sedation by the enteral route is unusual in intensive medicine. We analysed the feasibility/efficacy of long-term enteral sedation in ventilated critically ill patients. DESIGN:: Prospective interventional cohort study. SETTING:: General ICU. PATIENTS AND PARTICIPANTS:: Forty-two patients needing ventilation and sedation for at least 4 days. INTERVENTIONS:: At admission, sedation was induced with propofol or midazolam. Enteral hydroxyzine (± enteral lorazepam) was added in all patients within the second day. Intravenous drugs were gradually withdrawn, trying to maintain only enteral sedation after the initial 48 h. Analgesia was provided with continuous IV fentanyl. MEASUREMENTS AND RESULTS:: Sedation level was assessed evaluating, on a daily basis, patientsʼ compliance to the invasive care and comparing observed vs planned Ramsay scores three times a day. Excluding the first 2 days of patient-stabilisation and fast titration of sedation level, 577 days with ventilatory support were analysed. In 460 days (79.7%) total enteral sedation was given. This percentage rose to 94.2% when the requested Ramsay was 2 (347 days). Daily sedation was judged as adequate in 82.8% of days of total enteral sedation. Thirty-one patients had total enteral as the exclusive route of sedation. CONCLUSIONS:: After 24–48 h, enteral sedation may replace, totally/in part, IV sedation in ventilated patients. Total enteral sedation easily fits the target when a Ramsay score 2 is planned. When a deeper sedation is needed, a mixed regimen is effective and lowers IV drug dosages. No side effects were reported.