Abstract: By using cDNA microarray and RT‐PCR techniques, we investigated the genome‐wide alteration of gene expression in skin fibroblasts from patients with myoclonic epilepsy and ragged‐red fibers (MERRF) syndrome. By screening for the genes with altered levels of expression, we first discovered that matrix metalloproteinase 1 (MMP1) was highly induced in the primary culture of skin fibroblasts of a female patient in a four‐generation family with MERRF syndrome. This phenomenon was confirmed in skin fibroblasts from three other MERRF patients harboring about 85% of mtDNA with A8344G mutation. A further study revealed that the expression of MMP1 could be further induced by treatment of the skin fibroblasts with 200 μM hydrogen peroxide (H2O2) and inhibited by 1 mM N‐acetylcysteine. Moreover, the intracellular level of H2O2 in skin fibroblasts of the female MERRF patient was higher than those of the asymptomatic family members and age‐matched healthy controls. These findings imply that the increase in the expression of MMP1 may represent one of the responses to the increased oxidative stress in the skin fibroblasts of MERRF patients. We suggest that in affected tissues the oxidative stress‐elicited overexpression of MMP1, and probably other matrix metalloproteinases involved in cytoskeleton remodeling, may play an important role in the pathogenesis and progression of mitochondrial encephalomyopathies such as MERRF syndrome.