Epithelial ovarian cancer is the fifth leading cause of cancer mortality among women in the United States. For this disease, differences in age-adjusted incidence and survival rates between African American and Caucasian women are substantial. The objective of this study was to examine mtDNA sequence variants in 118 frozen tissues of three subtypes of epithelial ovarian cancer (serous, n = 48 endometrioid, n = 47 and mucinous, n = 23) and matched paracancerous normal tissues (n = 18) in relation to racial/ethnic and age differences. Restriction fragment length polymorphism (RFLP) and polymerase chain reaction (PCR)-based sequencing were used to evaluate two regions of mtDNA spanning 5317 to 7608 and 8282 to 10110 bp and including ND subunits 2, 3, MT-COI, II, and III, ATPase 8, a part of ATPase 6, and tRNA genes in frozen ovarian tissues obtained from the southern regional Cooperative Human Tissue Network (CHTN) and University of Alabama-Birmingham (UAB) Ovarian Spore Center. Thirty-nine mtDNA variants were detected of which 28 were previously unreported. One somatic variant of C9500T was observed. A variant, C7028T in the MT-CO1 gene, had an ascending frequency from borderline (8%) to stages III/IV (75%) among the three ovarian cancer subtypes and stages. It was found in 86% (42/49) of African-American and 43% (37/87) of the Caucasian women. A variant, T8548G in the ATPase 6 gene was detected at a frequency of 72% (18/25) in ovarian serous subtype tissues in stages III/IV. Of the African American patients under age 40, 95% (20/21) harbored the T8548G variant; this was in contrast to only 22% (8/35) of Caucasian patients in same age group. Variants C7256T and G7520A had a frequency of 54% (6/11) in endometrioid stage III; no corresponding variants were observed in mucinous subtype stage III. Furthermore, variants C7256T and G7520A were absent in serous ovarian cancer subtype. Interestingly, the C7520T variant in tRNA gene was present in 74% (36/49) of African American and 26% (23/87) of Caucasian patients. Taken together, our results suggest that, with respect to ethnic and age difference, these mtDNA variants may be involved in epithelial ovarian carcinogenesis. © 2008 Aikhionbare et al; licensee BioMed Central Ltd.