Background: Transforming growth factor-beta1 (TGF-β1), a member of transforming growth factor beta family, functions as a multi-functional cytokine and plays a key role in cellular growth, proliferation and differentiation. Aim of the work: To evaluate the role of TGF-β1 polymorphisms 509 C>T and TGF-β1 Gene expression in diagnosis of hepatocellular carcinoma (HCC) in cirrhotic Egyptian patients due to hepatitis C virus (HCV). Subjects and methods: Thirty five cirrhotic with HCC patients, thirty cirrhotic without HCC patients and 20 healthy volunteers were enrolled in this study. TGF-β1 gene expression in peripheral blood was quantitated using real-time polymerase chain reaction and molecular study of TGF-β1 509 C>T (rs1800469) polymorphism by Taqman allele discrimination was done for all subjects. Results: Showed that TGF-β1 -509 CT genotype was the most frequent genotype in HCC patients and the most frequent allele was T allele in HCC patients, without significant difference of TGF-β1 -509 polymorphism in the studied groups. TGF-β1 gene expression was significantly higher in HCC patients (mean 3.19±1.8) than in cirrhotic without HCC patients (mean 1.76±0.95) (p < 0.001) and normal controls (mean 1.00 ±0.8) (p < 0.001), and AFP ≥ 41 (ng/ml) and TGF-β1 gene expression ≥ 1.85 are diagnostic for HCC presence. Conclusion: TGF-β1 gene expression in the peripheral blood may be used as a molecular marker for HCC diagnosis, and TGF-β1 polymorphism 509 C>T was not associated with the risk of HCC in HCV-cirrhotic patients.