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Aim To study the role of matrix metalloproteinase (MMP- 1,2,3), inhibitor tissue inhibitors of metalloproteinase (TIMP)-2, and specific gene polymorphisms in unexpected poor ovarian responders (un-PORs). Materials and methods Group I consisted of 44 un-PORs, group II of 42 subfertile, normal ovarian responders (NORs), and group III of 66 fertile women in a prospective study. Matrix metalloproteinase-1,2,3 and TIMP-2 were assessed in 40 patients from groups I and II. Specific polymorphisms (SP; MMP-1 −519 A/G, MMP-2 −1575 G/A, MMP-3 −1171 5A/6A, and TIMP-2 rs55743137T/G) were investigated in group I, II, and III patients. Results Group I required similar amount of gonadotropins compared with group II, with fewer oocytes retrieved, lower fertilization rates, embryos/embryo transfer, clinical pregnancies/cycle, and “take-home babies” (p = 0.900, 0.001, 0.002, 0.001, 0.031, and p = 0.128) respectively, Table 1). Group I had lower MMP-2 with higher TIMP-2 (p = 0.002, 0.037 respectively; Table 2). In the same group, MMP-1 was higher in women with GG genotype of the MMP-1 polymorphism, vs GA genotype (p = 0.047; Table 3). The MMP-2, MMP-3, and TIMP-2 polymorphisms did not affect MMP-2, MMP-3, and TIMP-2 respectively. The same applied for MMP-1,2,3 and TIMP-2 in group II. Comparing frequencies of different genotypes of the MMP-1,2,3 and TIMP-2 polymorphisms, they did not differ between the three different groups: A, B, and C (Table 4). Conclusion Impaired MMP-2 activity, associated with significantly higher TIMP-2 detected, could be involved in un-POR pathogenesis. There was no strong association between MMP polymorphisms and un-POR susceptibility. However, women with A/G polymorphism (MMP-1 −519) had lower MMP-1 compared with GG homozygotes. Clinical significance Identification of patients with poor ovarian response in a pretreatment environment would help improve their ongoing fertility plan and manage their expectations. Also by having the ability to investigate if one belongs to that group, it could provide important family planning information for the patient. How to cite this article Tzafetas M, Lathouras K, Tantanasis T, Fidani S, Tziomalos K, Kalinderi K, Loufopoulos A, Zournatzi V. Role of Metalloproteinases in the Pathogenesis of Unexpected Poor Ovarian Response with a Possible Genetic Predisposition. Int J Infertil Fetal Med 2017;8(1):5-11.