OBJECTIVES: Critical illness can cause severe cognitive impairments. The objective of this trial was to assess the effect of nonsedation versus sedation with a daily wake-up call during mechanical ventilation on cognitive function in adult survivors of critical illness. DESIGN: Single-center substudy of the multicenter, randomized Non-sedation Versus Sedation With a Daily Wake-up Trial in Critically Ill Patients Receiving Mechanical Ventilation trial. Three months after ICU-discharge participants were tested for cognitive function by a neuropsychologist. SETTING: Mixed 14-bed ICU in teaching hospital. PATIENTS: A total of 205 critically ill, orally intubated, and mechanically ventilated adults. INTERVENTIONS: Patients were randomized within the first 24 hours from intubation to either nonsedation with sufficient analgesia or light sedation with a daily wake-up call during mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: A total of 118 patients survived to follow-up and 89 participated (75%). The participating survivors in the two groups did not differ regarding baseline data or premorbid cognitive impairments. Sedated patients had received more sedatives, whereas doses of morphine and antipsychotics were equal. The primary outcome was that no significant difference was found in the number of patients with mild/moderate cognitive impairments (six nonsedated patients vs four sedated patients) or severe cognitive impairments (16 nonsedated patients vs 17 sedated patients; p = 0.71). Secondary outcomes were cognitive test scores, and no differences were found between the scores in nonsedated and sedated patients. Hypothetical worst case scenarios where all patients, who had not participated in follow-up assessment, were assumed to have severe cognitive impairments were analyzed, but still no difference between the groups was found. We found more patients with delirium in the sedated group (96% vs 69% of patients; p = 0.002) and increased duration of delirium in sedated patients (median 5 vs 1 d; p < 0.001). Delirium subtypes were equally distributed between the groups, with hypoactive delirium most frequent (61%), followed by mixed delirium (39%). CONCLUSIONS: Nonsedation did not affect cognitive function 3 months after ICU-discharge.