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Introduction: Encephalitis presents with high morbidity and mortality in both HIV-infected and HIV-negative patients. There are currently no studies comparing HIV-infected and HIV-negative patients admitted to the hospital with acute encephalitis. Methods: We conducted a multicenter, retrospective study of adults admitted to the hospital with a diagnosis of encephalitis in Houston, Texas between 2005 and 2020. We describe the clinical manifestations, etiology, and outcomes of these patients with a focus on those infected with HIV. Results: We identified 260 patients with encephalitis, 40 of whom were infected with HIV. Viral etiology was identified in 18 of the 40 HIV-infected patients (45.0%); bacterial in 9 (22.5%); parasitic in 5 (12.5%); fungal in 3 (7.5%); immune-mediated in 2 (5.0%). Eleven cases had unclear etiology (27.5%). More than one disease process was identified in 12 (30.0%) patients. HIV-infected persons were more likely to have neurosyphilis (8/40 vs. 1/220; OR 55; 95%CI 6.6–450), CMV encephalitis [5/18 vs. 1/30; OR 11.2 (1.18–105)], or VZV encephalitis (8/21 vs. 10/89; OR 4.82; 1.62–14.6) compared to the HIV-negative patients. Inpatient mortality was similar in the HIV-infected and HIV-negative patients, 15.0% vs 9.5% [p = 0.4, OR 1.67 (0.63–4.44)], but one-year mortality was higher for the HIV-infected patients, 31.3% vs 16.0% [p = 0.04, OR 2.40 (1.02–5.55)]. Conclusion: This large, multicenter study shows that HIV-infected patients with encephalitis have a distinct pattern of disease when compared with HIV-negative patients, and that this population has nearly twice the odds of mortality in the year following hospitalization. [ABSTRACT FROM AUTHOR]