Abstract Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. The most common underlying causes of Hepatocellular car-cinoma (HCC) are chronic liver diseases and cirrhosis. Aim of Study: Our study aimed to investigate the serum estradiol levels in patients with nonalcoholics steatohepatitis (NASH) related HCC and to explore their correlations with clinicopathological features of HCC. Patients and Methods: A Controlled Cross-Sectional Study included 200 patients with NAFLD (181 patients with NAFLD and 23 patients with NAFLD related HCC) and 50 controls. Serum estradiol was measured by enzyme-linked immuno-sorbent assay (ELISA). Results: The serum level of estradiol was significantly lowered in patients with NAFLD (32.24±7.3pg/ml) compared to controls (42.9±3.9pg/ml). Moreover, our findings revealed lower concentrations of serum estradiol in the HCC group (28.6±5.3pg/ml) compared to the NAFLD group (33.45 ±4.3pg/ml, p<0.00 1). We found significant negative correla-tions between serum estradiol levels and clinicopathological features of HCC (portal vein thrombosis, lymph node metas-tasis, number of tumor lesions, advanced clinical stage, tumor size, tumor site, distant metastasis) in patients with NAFLD complicated with HCC. linear regression test and we observed that serum triglycerides and a-fetoprotein were significantly associated with serum estradiol among the HCC group. Conclusion: Serum estradiol level was significantly low-ered in the HCC subgroup compared to the NAFLD group and negatively correlated with clinicopathological features of HCC. Serum estradiol can be used as a promising predictor of HCC in female patients with NAFLD.