Background: Pregnancy is the process from the fertilized ovum to the fetus with capability of extra uterine survival. Pregnancy loss is the most common complication of pregnancies. Advances in the detection of early pregnancy revealed that about 70% of human conceptions fail to achieve viability but clinically recognized pregnancies terminate as a miscarriage in about 15% of cases. About 1 in 300 couples and 0.5-2% of women are involved in repeated pregnancy loss (RPL). Various etiological factors involve in RPL and the main part of them remains unknown. Among them the genetic factors are important. The apoptotic changes and the aberrant expression of many genes including apoptotic related genes were seen in RPL.Materials and Methods: Familial pedigrees of 335 consecutive couples suffering from RPL were initially evaluated at a primary stage. Among them, 96 women were screened as idiopathic at reproductive age. Molecular genetic variations in internal apoptotic related genes BAX, BCL2 and mitochondrial genome were investigated in comparison to control group. The methods were PCR-SSCP, PCR-Digestion-SSCP, Multiplex PCR and PCR-Direct sequencing. Results: The evaluation of familial pedigree of 335 RPL couples showed 120 cases of RPL in female relatives and 76 cases in male relatives. Other families with RPL were seen in two or three consecutive generations in 15.6% of female relatives. At least two cases of RPL in other consanguineous marriages were observed in 4.2%. There were familial marriages in 51.6% of RPL women and 21.8% of control group (p=0.0003). A statistically significant association was observed between the study and the control groups with regard to the frequency of alleles A to G (97.76% in RPL and 90.71% in control group) at nucleotide -179 in Bax promoter region (p=0.013). G90C and G95A transitions were found in the coding region of exon 1 that change amino acid Glutamine (Q) to Histidine (H) and Arginine (R) to lysine (K) respectively. A statistically significant association was observed between H allele (p=0.0001) and K allele (p<0.0001) and the occurrence of RPL. Two nucleotide variations were seen in molecular analysis of Bcl2 gene. The G66C alteration in all RPL and normal women and A735G in 36.46% of RPL cases and 43.75% of control group (p=0.1449). No deletions but a high frequency of point mutations were found in RPL females; some 129 variations were observed in RPL. The mean of the Dloop mutations was 8.79 and 4.90 in RPL and control group respectively (ANOVA=0.0001). Among them, 22 mutations were significant in RPL group and the insertion of C in nucleotide 114 was novel. D310 point mutations were seen in 51.04% of RPL women and 61.46% of control women. There were 4 variations in tRNA thr consisting of G15930A novel mutation. Also, a novel T15972C mutation was seen in tRNA pro. Conclusion: The high frequency of RPL in maternal pedigree implicates the maternal background of the disorder. On the other hand, there were higher rate of familial repeats of abortion, RPL repeats and consanguineous marriage in RPL pedigrees. Such evidences show the genetic background. However, pedigree analysis has critical role in the approach of RPL women. Our result indicates a supportive role of RPL for A-179G mutation in Bax gene, but two polymorphisms, G90C and G95A found in exon 1, provide a susceptible background for promoting miscarriages. We believe that Bax gene has an important role in pregnancy loss. But, the Bcl2 alterations don’t reflect any association in RPL. The RPL women did not have any deletions in mitochondrial genome. Deletions can lead to the early apoptosis, elimination of the cells and fetal loss. Although, we did not find any deletions in RPL women, investigating this issue in the aborted fetus as well could provide further information. High rates of mutations in D-Loop of mtDNA were observed in maternal blood, a fact that may have a direct or indirect role in inducing RPL. There were 7 significant point mutations consisting of T16126C, T16189C, C16223T, C16294T, T16311C, T16362C, and T16519C more frequent in RPL females compared to the controls. Among 89 point mutations that were only detected in RPL group, C114 insertion was novel. Also, 15 variations consisting of T146C, C150T, C151T, T152C, T195C, T199C, C285T, C295T, C462T, T489C, C16069T, T16093C, C16148T, A16183C, and C16261T were significant in this group. These variations can have important roles in RPL, independently or as a part of haplogroups. The difference of D310 mutation between two studied groups was not significant. Disease-related point mutations could potentially influence mitochondrial tRNA and affect their primary, secondary, and tertiary structure. It leads to protein synthesis defects and, in turn, mitochondrial dysfunction. Ultimately, these disturbances result in cellular dysfunction which is more important in cell proliferation and development. It seems more studies on these significant mutations can lead to the presentation of a diagnostic panel for RPL patients. Furthermore, preclinical abortions which are usually reported as infertile couples, and also failure of in vitro fertilization are our next targets for expanding this research to infertility.