Microsomal epoxide hydrolase enzyme is involved in xenobiotics detoxification. It catalyzes the phase I hydrolysis of epoxides and plays a role in the detoxification processes and in the metabolism of endogenous and exogenous compounds. Exposure to various environmental toxins with a reduced ability to metabolize them may lead to acquired aplastic anemia (AAA). Individuals vary in their ability to metabolize several DNA-damaging agents due to polymorphisms of biotransforming enzymes. Two variants of human epoxide hydrolase enzyme with different enzyme activity have been described; exon 3 polymorphism is associated with lower enzyme activity whereas exon 4 polymorphism is associated with higher activity. The present study assessed the genetic polymorphisms of the microsomal epoxide hydrolase enzyme (mEPHX) and detected their impact on the susceptibility, disease severity, and prognosis in Egyptian patients with AAA. The mEPHX 113 Tyr-His and 139 His-Arg genotypes were determined by PCR-RFLP, in 50 patients with AA as well as 50 age and sex matched healthy control subjects. Our study revealed that both mEPHX 113 Tyr-His and mEPHX 139 His-Arg genes polymorphism were associated with increased risk of developing aplastic anemia with OR 3.188, 6.048 and 95% CI 1.403-7.241, 2.540-14.399 respectively, and have a significant impact on the prognosis by increasing the risk of bad outcome with OR 26.000, 6.111 and 95% CI 5.690-118.06, 1.666-22.493 respectively. Moreover, when combining the 2 genes polymorphism, a significant elevation of the risk of developing aplastic anemia and bad outcome was found. Also they were correlated with the clinical presentation and laboratory data. In conclusion, mEPHX 113 Tyr-His and 139 His-Arg genes polymorphism could be involved in the pathophysiology and development of acquired aplastic anemia in Egypt. Also, they may have clinical relevance and may be useful as predictive molecular markers for prognosis and disease outcome in AAA patients.