Abstract: Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes （MELAS） is a maternally inherited mitochondrial disease with diverse clinical manifestations, which is likely to be misdiagnosed as herpes simplex encephalitis （HSE）. In this article, one case of MELAS who was initially misdiagnosed as HSE was reported. The patient was admitted due to recurrent fever, headache, limb convulsion for 1 month and recurrent headache for 1 week. Upon admission, the patient was suspected with HSE and untreated with antiviral therapy. Subsequent blood and urine genetic testing confirmed the diagnosis of MELAS. MELAS shares similar manifestations with atypical HSE, which should be differentiated with cautions. Elevated cerebrospinal fluid and/or serum lactic acid levels and basal ganglia calcification contribute to the diagnosis of MELAS. The mitochondrial DNA mutation in MELAS patients can be easily detected by the blood and urine genetic testing without the need for invasive procedures, such as muscle biopsy.