Background: Guidelines recommend rest periods between nursing interventions for patients with a neurologic diagnosis but do not specify a safe number of interventions. Objectives: To examine the physiological stress response to clustered nursing interventions in neurologic patients receiving mechanical ventilation. Methods: Prospective, comparative, descriptive design to examine effects of clustered interventions (≥6 interventions in a single nursing interaction) versus nonclustered interventions on patients' stress. Stress response was defined as a 10% change in end-tidal carbon dioxide from before the interaction to (1) 5 and 10 minutes after the start of the interaction, (2) at the end of the interaction, and (3) 15 minutes after the interaction. Results: The mean percent change in end-tidal carbon dioxide at 5 minutes differed significantly between patients with clustered interventions and patients with nonclustered interventions (6.7% vs -0.2%; P = .001). Patients with clustered interventions were significantly more likely than patients with low clustering to exhibit a stress response at 5 minutes (24.3% vs 0%; P = .01). Conclusions: Neurologic patients receiving mechanical ventilation who experienced 6 or more clustered nursing interventions showed a higher mean change in end-tidal carbon dioxide than did patients who received fewer than 6 clustered interventions. These findings suggest that providing fewer interventions during 1 nursing interaction may minimize induced stress in neurologic patients receiving mechanical ventilation. (American Journal of Critical Care. 2013;22:239-245).