A previously healthy, 24-year-old man presented to the emergency department reporting chills, diffuse pain, and malaise. After a diagnosis of “viral illness,” he was discharged, taking diphenhydramine hydrochloride as needed (up to 100 mg daily). Abruptly, 3 days after first presentation, he became agitated and incoherent. He returned to the emergency department where his temperature was 98°F, blood pressure was 157/115 mm Hg, and pulse was 65 beats/min. He was hypervigilant, combative, and nonsensical. Cranial nerve function, pupillary size, limb strength, coordination, and reflexes were normal. A toxic reaction to diphenhydramine likely contributed but his delirium failed to clear over 2 days despite its discontinuance. His initial agitation responded only partially to 10 mg of intramuscular haloperidol and 10 mg of intravenous lorazepam. Computed tomography (CT) of the head showed no inflammatory lesions, hypodense areas, hydrocephalus, or abnormal contrast enhancement. A preexisting asymptomatic bullet fragment deep in the parietal white matter contraindicated magnetic resonance imaging. Intravenous acyclovir, ceftriaxone sodium, vancomycin hydrochloride, ampicillin, and dexamethasone were used as early therapy.