Epilepsy is an associated feature of patients with the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). A substitution at nucleotide position 3243 A>G of the mitochondrial DNA is the most common mutation encountered both in Caucasians and in Chinese/Taiwanese. We herein report a 38-year-old man with A3243G mutation of the mitochondrial DNA whom developed MELAS. The manifestation of his focal motor epilepsy was aggravated by use of sodium valproate (VPA). The mechanism of this paradoxical effect is proposed.