This study evaluates the role of PNPLA3 gene polymorphism (rs738409) by PCR/ Taqmanassay in 75chronic HCV patients (50 with HCC and 25without) and 25 controls. Thetestedadi ponutrin single nucleotide polymorphism (SNP) showed that the C allele of PNPLA3 (rs738409) gene is common in all groups than G allele and higher in HCC (95%) than cirrhotic (80%) and controls (72%). Frequency of HCC was higher for patients with CC genotype (90%), than those with CG (10%) and GG genotype (0%). The study detected highly statistically significant difference between HCC and cirrhotic groups as regard CC genotype about 4.2 folds (p=0.04) and C allele (p=0.004).Also, CC genotype is more prominent in cirrhotic patients (68%) than controls group (52%) but difference not significant. In Conclusion these results suggest that PNPLA3 (rs738409) polymorphism with CC genotype was significantly associated with liver cirrhosis and increased risk to develop, HCC in Egyptian patients with chronic hepatitis C infection.