BackgroundHepatocellular carcinoma (HCC) is one of the most common causes of cancer-mortality globally. Hepatocarcinogenesis is a complex multifactorial process. Host genetic background appeared to play a crucial role in the progression of HCC among chronic hepatitis C patients, especially in the era of Genome Wide Association Studies (GWAS) which allowed us to study the association of millions of single nucleotide polymorphisms (SNPs) with different complex diseases. This article aimed to review the discovered SNPs associated with the risk of HCV-related HCC development which was reported in the published GWA studies and subsequent validation studies and also try to explain the possible functional pathways.Main textWe reviewed the recent GWA studies which reported several new loci associated with the risk of HCV-related HCC, such as (SNPs) in MHC class I polypeptide-related sequence A (MICA), DEP domain-containing 5 (DEPDC5), Tolloid-like protein 1 (TLL1), and human leukocyte antigen (HLA) genes. We also explained the possible underlying biological mechanisms that affect the host immune response pathways. Additionally, we discussed the controversial results reported by the subsequent validation studies of different ethnicities.ConclusionsAlthough GWA studies reported strong evidence of the association between the identified SNPs and the risk of HCV-related HCC development, more functional experiments are necessary to confirm the defined roles of these genetic mutations for the future clinical application in different populations.