Abstract Background: Infertility is a major problem that is very challenging for scientists, as numerous causes are reported as idiopathic. Genetic, viral, anatomical, immunological and environmental factors can all play a role in infertility. Male factors account for almost 50% of infertility cases, genetic abnormalities either structural or numerical account for almost 10 to 15% of the problem. While Klinefelter syndrome is considered the most common genetic cause of male infertility, microdeletions of azoospermia factors (AZF) on the long arm of the Y chromosome are the second common. AZF locus carries the genes responsible for spermatogenesis, hence any microdeletion in the subregions of the AZF locus, AZFa, AZFb or AZFc will result in severe oligospermia or azoosper-mia, consequently infertility. The role of geographical and ethnic variations in the frequency of AZF microdeletions is still debatable. Aim of Study: To evaluate the frequency of Y chromosome microdeletions in AZF loci in Egyptian men. Thirteen markers in AZF regions were tested; AZFa (sY86, sY87, sY615), AZFb (sY127, sY134, sY142), AZFc (sY197, sY254, sY255, sY1291, sY1125, sY1206, sY242) and analyzed for its clinical signif-icance in infertile Egyptian men. Patients and Methods: This case-control study was con-ducted in the Andrology and Clinical Pathology Departments; Faculty of Medicine, Cairo University. In this research, fifty infertile men (19-50 years) who are unable to have children in spite of having frequent non protective sexual intercourse for more than 2 years, were included as cases, while 50 age-matched males as controls. Each subject was tested for thirteen markers in AZF region to determine their association and role, if any, in infertility. Genes in each of the AZFa, AZFb, AZFc subregions were tested and analyzed by Real Time polymerase (PCR) according to established protocols. Results: Among the 50 infertile men screened for micro-deletion, twenty subjects are found to have microdeletions (40%) which is statistically significant (p-value <0.001), seven of which show at least one microdeletion, the rest range from two to ten microdeletions. The frequency of AZFa microde-letion is not significant (p-value = 0.495), however AZFb and AZFc microdeletions are significantly present (p-value = 0.006 and <0.001, respectively). The overall frequency of AZFc microdeletions is the most prevalent (38%). The highest frequency of microdeletion is observed in genes Y1291 on the AZFc locus (26%) which is considered statistically signif-icant with p-value <0.001. Subjects with combined AZFa microdeletion with either AZFb or AZFc are not statistically significant. Nevertheless, combined AZFc and AZFb micro-deletion are statistically significant with p-value <0.001. AZF microdeletions are not observed in any of the control subjects. Conclusion: Our results suggest that the frequency of Y chromosome AZF microdeletions, especially AZFc microde-letions, is elevated in Egyptian males with severe sperma-togenic failure and hence a high risk of infertility.