Background: Hepatocellular carcinoma is the most common primarytumor of the liver. The molecular determinants of the HCC progression arestill under investigation. p53 plays a major role in more than 50% ofhuman cancers including HCC. Genetic polymorphisms of the Murine-Double-Minute 2 (MDM2) can modulate MDM2 expression to affect p53which acts as a tumor suppressor gene and cause increase in the tumorprogression.Aim of the work: The aim of this study is to investigate the interrelationbetween p53 Arg72Pro polymorphism and MDM2 T309G SNP and theirrole in the incidence of HCC in the Egyptian population.Subjects and Methods: Genotyping of the candidate genes was performedby Real-Time PCR assay in 50 HCC patient and 50 subjects as a controlgroup.Results: The frequencies of genotype GG, genotype GC and genotype CCof p53 Arg72Pro polymorphism among the HCC cases were 12.0%(6/50), 50.0% (25/50) and 38.0% (19/25) respectively and that in thecontrol group were 8.0% (4/50), 48.0% (24/50) and 44.0% (22/50)respectively. There was no significant difference in between the twostudied groups with p value 0.726. There was no relation between p53Arg72Pro polymorphism and the HCC risk (For CC versus CG/GG, OR= 0.780, 95%CI 0.351-0.1.; For CC/CG versus GG, OR = 0.638, 95%CI0.168-2.413 with p value 0.542 and 0.505 respectively). The frequenciesof genotype TT, genotype TG and genotype GG of MDM2 SNP309among the HCC cases were 28.0% (14/50), 52.0% (26/50) and 20.0%(10/50) respectively and that in the control group were 26.0% (13/50),50.0% (25/50), 24.0 (12/50) respectively. There was no significantdifference in between the two studied groups with p value 0.888. There was no relation between MDM2 T309G polymorphism and the HCC risk(For GG versus TG/TT, OR = 0.792, 95%CI 0.306-2.046; For GG/TGversus TT, OR = 1.0, 95%CI 0.409-2.444 with p value 0.629 and 1.0respectively). HCC patient AFP showed significant difference whencompared to control group with the median for the HCC patients in AFPlevel is 340.1 (124.5-590.5) (ng/mL) while the median for the controlgroup is 11.5 (4.8-18.5) (ng/mL) (p value = 0.048).Conclusion: The current study has shown that the association between p53Arg72Pro genotype and MDM2 T309G SNP genotype and HCC in thecohort study in Egyptian population is not significant.