Objective: To characterize clinical features, neuroimaging, and outcomes of herpes simplex encephalitis (HSE) in immunocompromised individuals. Methods: We performed a retrospective case control review of patients diagnosed with HSE. Adult patients were dichotomized into immunocompromised (n = 14) and immunocompetent groups (n = 15). Results: Fewer immunocompromised patients presented with prodromal symptoms and focal deficits. While the majority of CSF profiles in the immunocompromised patients were mononuclear cells predominant, 3 had polymorphonuclear predominance and another 3 had normal profiles. MRI showed widespread cortical involvement, with brainstem or cerebellar involvement in some. Two immunocompromised patients had recurrent HSE. The immunosuppressed state was associated with a decrease in Karnofsky Performance Status Scale (KPSS) score of 23.1 (p = 0.018). Every 1-day delay in initiation of acyclovir was associated with a decrease in KPSS of 10.2 (p = 0.002), and every 10 cell/mm3 increase of CSF leukocytosis was associated with an increase in KPSS of 0.7 (p = 0.009). Mortality rate was 6 times higher in the immunocompromised patients. Conclusions: Immunocompromised states may predispose to HSE with atypical clinical and neuroradiologic features. Immunocompromised individuals with HSE have significantly worse outcomes and mortality. Early diagnosis and treatment is associated with improved outcome. The findings are particularly important in light of the increasing use of potent immunosuppressive and immunomodulatory therapies.