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Inefficient mitochondrial electron transport chain (ETC) function has been implicated in the vicious cycle of reactive oxygen species (ROS) production that may predispose an individual to late onset diseases, such as diabetes, hypertension, and cancer. Mitochondrial DNA (mtDNA) variations may affect the efficiency of ETC and ROS production, thus contributing to cancer risk. To test this hypothesis, we genotyped 69 mtDNA variations in 156 unrelated European-American females with familial breast cancer and 260 age-matched European-American female controls. Fisher's exact test was done for each single-nucleotide polymorphism (SNP)/haplogroup and the P values were adjusted for multiple testing using permutation. Odds ratio (OR) and its 95% confidence interval (95% CI) were calculated using the Sheehe correction. Among the 69 variations, 29 were detected in the study subjects. Three SNPs, G9055A (OR, 3.03; 95% CI, 1.63-5.63; P = 0.0004, adjusted P = 0.0057), A10398G (OR, 1.79; 95% CI, 1.14-2.81; P = 0.01, adjusted P = 0.19), and T16519C (OR, 1.98; 95% CI, 1.25-3.12; P = 0.0030, adjusted P = 0.0366), were found to increase breast cancer risk; whereas T3197C (OR, 0.31; 95% CI, 0.13-0.75; P = 0.0043, adjusted P = 0.0526) and G13708A (OR, 0.47; 95% CI, 0.24-0.92; P = 0.022, adjusted P = 0.267) were found to decrease breast cancer risk. Overall, individuals classified as haplogroup K show a significant increase in the risk of developing breast cancer (OR, 3.03; 95% CI, 1.63-5.63; P = 0.0004, adjusted P = 0.0057), whereas individuals bearing haplogroup U have a significant decrease in breast cancer risk (OR, 0.37; 95% CI, 0.19-0.73; P = 0.0023, adjusted P = 0.03). Our results suggest that mitochondrial genetic background plays a role in modifying an individual's risk to breast cancer.