We present a case of serious antidepressant discontinuation syndrome (ADDS) in a 72- year-old woman in the intensive care unit (ICU). Although this syndrome may be mild under ambulatory conditions, ICU patients can experience serious neurocognitive symptoms that are difficult to differentiate from delirium. We report delayed recognition of the ADDS in a patient in the ICU who was initially diagnosed with severe hyperactive delirium. Subsequent to hiatal hernia surgery, the patient was admitted to the ICU for aspiration and was intubated. Due to increasing agitation the patient received high doses of dexmedetomidine, fentanyl, midazolam, and propofol. The patient was treated with high doses of a serotonin norepinephrine reuptake inhibitor (SNRI) antidepressant, duloxetine, for 2 years. However, the antidepressant was not effectively administered postsurgically due to gastroparesis. The signs and symptoms of ADDS can occur cryptogenically if they are partially masked by sedating agents. Due to concern for the discontinuation syndrome and the inability to administer duloxetine via a nasogastric tube, another SNRI, venlafaxine, was administered. Venlafaxine administration allowed unexpectedly prompt dose reduction and then total discontinuation of all sedating agents, allowing liberation from mechanical ventilation and ICU discharge. This case illustrates the importance of avoiding antidepressant discontinuation in the ICU.