Background: Most herpes simplex virus encephalitis (HSVE) patients become disabled despite antiviral therapy. Adjunctive corticosteroid therapy may improve outcomes. Methods: This was a systematic review of the literature addressing the use of corticosteroids in HSVE. Results: Data suggesting that steroids decrease the immunological response and enhance viral replication originated from non-neural microenvironments. Early steroid administration might be harmful because initial damage in HSVE is mediated by viral replication. Steroid treatment improves outcomes in animal models by inhibiting the subsequent inflammatory response. Clinical observations support a similar benefit in symptomatic HSVE patients. Cerebrospinal fluid inflammatory markers might guide appropriate timing in future clinical practice. Conclusions: Experimental and clinical observations suggest a benefit from adjunctive steroid therapy in HSVE. Nevertheless, current evidence is not yet sufficient to endorse this approach as a standard of practice. © 2014 International Medical Press 1359-6535.