Hepatocellular carcinoma (HCC) is the most prevalent and life-threatening form of liver cancer worldwide. In Egypt, HCC ranks as the second most common cancer in men and the sixth most common in women. This study investigated the association between DEPDC5 and PNPLA3 variants and the risk of developing HCC. One hundred HCC patients related to HCV infection and 100 healthy controls were enrolled. Single nucleotide polymorphisms (SNPs) for DEPDC5 (rs1012068) and PNPLA3 (rs738409) were analyzed using real-time PCR. The DEPDC5 variants were significantly associated with the development of HCC. Mutant and heterozygous genotypes of DEPDC5 were significantly associated with HCC (OR = 15.98 [95% CI: 5.53-46.13], p < 0.001; OR = 6.04 [95% CI: 3.08-11.84], p < 0.001, respectively). However, the PNPLA3 polymorphism was not associated with HCC risk. Nevertheless, the PNPLA3 SNP was significantly correlated with HCC in individuals with elevated AFP levels (p = 0.026). These findings suggest that the DEPDC5 could serve as an indicator for diagnosing the progression of liver diseases to HCC in HCV patients in Egypt. Additionally, PNPLA3 polymorphisms may play a role in the progression and severity of HCC, especially in cases with elevated AFP levels.