A 54-year-old woman was admitted to the hospital suffering from fever and personality changes. Laboratory examination of her cerebrospinal fluid (CSF) showed 270 mononuclear cells, 30 polynuclear cells and a clinically low number of erythrocytes/mm3. Empirical clinical findings from this case suggested treatment with acyclovir. Magnetic resonance imaging (MRI) showed bilateral temporal hyperintense signals in T2-weighted images. PCR with specific primer for herpes simplex virus type 1 (HSV-1) and HSV-2 were negative. There was no elevation of oligoclonal antibodies specific to HSV in CSF after 2 weeks. Although we did not prove the presence of the agent microbiologically at the clinical onset of the disease, the MRI and electroencephalogram (EEG) findings, erythrocytes in CSF and the dramatic response to acyclovir therapy are suggestive of a diagnosis of herpes simplex encephalitis (HSE).