Abstract It is known that point mutations and rearrangements (deletions and duplications) of mammalian mitochondrial DNA (mtDNA) can result in mitochondrial dysfunction and human disease. Very little attention has been paid to mtDNA circular dimers (a complex form consisting of two genomes joined head-to-tail) despite their close association with human neoplasia. MtDNA dimers are frequently found in human leukemia, but the clinical relevance of their presence remains unknown. To begin to investigate the role of circular dimer mtDNA in the tumorigenic phenotype, we have created isogenic cell lines containing monomer and dimer mitochondrial genomes and compared the respective nuclear mRNA expression using Affymetrix gene array analysis. Surprisingly, a large number of nuclear gene changes were observed, with one of the largest category of genes being associated with remodeling of the cell surface and extracellular matrix. Since cell growth, migration, apoptosis, and many other cellular processes are influenced by signals initiating from the cell surface, the changes associated with the presence of mtDNA dimers could lead to significant alterations in tumorigenic potential and/or progression.