Background:Given that risk for hepatocellular carcinoma (HCC) is linked to liver cirrhosis. There is accumulating evidence that estrogen influences liver function via estrogen receptors (ERs), which are dysregulated in many cancers all over the body. Objective: We aimed to investigate the ESR2 genes (rs1256049 and rs-4986938) polymorphism and mRNA expression in patients with nonalcoholic fatty liver (NAFLD), in correlation with the risk and progression of HCC among Egyptian women with NAFLD. Patients and Methods:Case-control study enrolled fifty women with NAFLD and fifty healthy women.  Serum E2 level was determined using ELISA. Genotyping of ESR2-SNPs (rs1256049 and rs4986938) was performed by PCR-RFLP. ERβ2 mRNA values were explored by RT- PCR. Results: There were non-significant differences concerning ERβ2 mRNA expression levels among studied groups. Concerning genotype of ESR2 (rs1256049), in NAFLD group the frequencies of the AA, GA were higher than in controls (OR = 22.62,95% CI = 2.8- 182.6, P ˂0.001 and OR = 8.7,95% CI = 1.77- 42.69, P ˂0.001 respectively). Additionally, A allele OR = 13.5,95% CI = 4.58- 39.76, P ˂0.001). There were non-significant differences in frequencies of GG, GA, and A allele between case and control groups P >0.001. Regarding ESR2 (rs1256049), the only significant parameter was A allele OR = 4.71,95% CI = 1.96-11.33, P ˂0.001 in cirrhotic NAFLD compared to non-cirrhotic NAFLD. ESR2 (rs1256049) polymorphism was significantly higher in HCC. Thus, it could be a predictor of HCC among NAFLD patients. BMI, HOMA-IR, E2, and FIB-4 scores were highly correlated with HCC in both cirrhotic and non-cirrhotic NAFLD groups by applying a logistic regression test. Conclusion: ESR2 (rs1256049) polymorphism was significantly higher in HCC. Thus, it could be a predictor of HCC among NAFLD patients.