The aim of this study was to determine the existence of association between the genetic polymorphisms of metabolizing genes GSTM-1, GSTT-1,and NAT-2,and the presence of mitochondrial genome instability (mtGI) in breast cancer cases. Ninety-four pairs of tumoral/nontumoral breast cancer samples were analyzed. Our samples showed 40.42% of mtGI by analysis of two D-loop region markers, a (CA)n mtMS starting at the 514-bp position, and four informative MnlI sites between the 16, 108-16, 420-bp. GSTM-1null genotype has shown a significant association with mtGI presence (χ2 = 7.62; P= 0.006) in breast cancer cases; moreover, these genotypes also are related to an increased risk for mtDNA damage (odds ratio (OR) = 3.71 (1.41-9.88); 95% Cornfield confidence interval (CI)). These results suggest that the absence of GSTM-1enzymatic activity favors chemical actions in damaging the mtDNA. Analysis of GSTT-1and NAT-2polymorphisms showed no association with mtGI (χ2 = 0.03; P = 0.87 and χ2 = 2.76; P = 0.09, respectively). The analysis of invasive breast cancer cases showed mtGI in 74.36% of ILC cases (29 of 39 samples), and in only 18.75% (9 out of 48) IDC cases; this result suggests a possible relation between mtDNA mutations and variations in molecular pathways of tumor development.Instituto Multidisciplinario de Biología CelularFacultad de Ciencias Médica